Ocular implant with therapeutic agents and methods thereof

ABSTRACT

Implants and methods for treating ocular disorders are provided. One method involves introducing an implant into an anterior chamber of an eye. The implant is implanted into eye tissue adjacent the anterior chamber such that a proximal end of the implant resides in the anterior chamber following implantation. A therapeutic agent is eluted from the implant into the eye. Desirably, the release of the therapeutic agent from the implant is controlled. The controlled release of the therapeutic agent can be at a chosen rate and/or for a selected duration which can be episodic or periodic. The therapeutic agent can be an antiproliferative agent, an anti-inflammatory drug, or a compound for treating glaucoma or ocular hypertension.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 14/754,458, filed Jun. 29, 2015, which is acontinuation of U.S. patent application Ser. No. 13/716763, filed Dec.17, 2012, which is a continuation of U.S. patent application Ser. No.12/772,889, filed May 3, 2010, entitled “Ocular Implant With TherapeuticAgents And Methods Thereof,” which is a continuation application of U.S.patent application Ser. No. 10/706,300, filed Nov. 12, 2003 (the“10/706,300 application”), now U.S. Pat. No. 7,708,711 B2, issued May 4,2010, entitled “Ocular Implant With Therapeutic Agents And MethodsThereof,” which is a continuation-in-part of U.S. patent applicationSer. No. 10/395,633, filed Mar. 21, 2003, now abandoned, entitled “StentWith Drug Coating,” which is a continuation application of U.S. patentapplication Ser. No. 09/549,350, filed Apr. 14, 2000, now U.S. Pat. No.6,638,239 B1, issued Oct. 28, 2003, entitled “Apparatus And Method ForTreating Glaucoma.”

The Ser. No. 10/706,300 application is also a continuation-in-part ofU.S. patent application Ser. No. 10/634,213, filed Aug. 5, 2003, nowU.S. Pat. No. 7,867,186 B2, issued Jan. 11, 2011, entitled “Devices AndMethods For Treatment of Ocular Disorders,” which is acontinuation-in-part of U.S. patent application Ser. No. 10/118,578,filed Apr. 8, 2002, now U.S. Pat. No. 7,135,009 B2, issued Nov. 14,2006, entitled “Glaucoma Stent And Methods Thereof For GlaucomaTreatment,” which claims the priority benefit of U.S. ProvisionalApplication No. 60/281,973, filed Apr. 7, 2001. The aforementioned U.S.patent application Ser. No. 10/634,213 also claims the priority benefitsof U.S. Provisional Application No. 60/401,166, filed Aug. 5, 2002, andU.S. Provisional Application No. 60/451,226, filed Feb. 28, 2003.

The Ser. No. 10/706,300 application is also a continuation-in-part ofU.S. patent application Ser. No. 10/046,137, filed Nov. 8, 2001, nowabandoned, entitled “Drug-Releasing Trabecular Implant for GlaucomaTreatment,” which claims the priority benefit of U.S. ProvisionalApplication No. 60/281,247, filed Apr. 3, 2001.

The Ser. No. 10/706,300 application also claims the priority benefits ofU.S. Provisional Patent Application No. 60/425,911, filed Nov. 12, 2002,and U.S. Provisional Patent Application No. 60/431,918, filed Dec. 9,2002.

This application claims priority to all of the aforementioned prioritydocuments, the entireties of all of which are hereby incorporated byreference herein.

BACKGROUND OF THE INVENTION Field of the Invention

The present application relates generally to medical devices and methodsfor reducing the intraocular pressure in an animal eye and, moreparticularly, to shunt-type stenting devices for permitting and/orenhancing aqueous outflow from the eye's anterior chamber towardexisting outflow pathways and associated methods thereof for thetreatment of glaucoma in general. Furthermore, the invention relates tothe delivery of bioactive agents to ocular tissue from an implant.

Description of the Related Art

The human eye is a specialized sensory organ capable of light receptionand able to receive visual images. The trabecular meshwork serves as adrainage channel and is located in the anterior chamber angle formedbetween the iris and the cornea. The trabecular meshwork maintains abalanced pressure in the anterior chamber of the eye by allowing aqueoushumor to flow from the anterior chamber.

About two percent of people in the United States have glaucoma. Glaucomais a group of eye diseases encompassing a broad spectrum of clinicalpresentations, etiologies, and treatment modalities. Glaucoma causespathological changes in the optic nerve, visible on the optic disk, andit causes corresponding visual field loss, resulting in blindness ifuntreated. Lowering intraocular pressure is a major treatment goal inall glaucomas.

In glaucomas associated with an elevation in eye pressure (intraocularhypertension), the source of resistance to outflow of aqueous humor ismainly in the trabecular meshwork. The tissue of the trabecular meshworkallows the aqueous humor (“aqueous”) to enter Schlemm's canal, whichthen empties into aqueous collector channels in the posterior wall ofSchlemm's canal and then into aqueous veins, which form the episcleralvenous system. Aqueous humor is a transparent liquid that fills theregion between the cornea, at the front of the eye, and the lens. Theaqueous humor is continuously secreted by the ciliary body around thelens, so there is an essentially constant flow of aqueous humor from theciliary body to the eye's anterior chamber. The anterior chamberpressure is determined by a balance between the production of aqueousand its exit through the trabecular meshwork (major route) or uvealscleral outflow (minor route). The trabecular meshwork is locatedbetween the outer rim of the iris and the back of the cornea, in theanterior chamber angle. The portion of the trabecular meshwork adjacentto Schlemm's canal (the juxtacanalicular meshwork) causes most of theresistance to aqueous outflow.

Glaucoma is grossly classified into two categories: closed-angleglaucoma, also known as “angle closure” glaucoma, and open-angleglaucoma. Closed-angle glaucoma is caused by closure of the anteriorchamber angle by contact between the iris and the inner surface of thetrabecular meshwork. Closure of this anatomical angle prevents normaldrainage of aqueous humor from the anterior chamber of the eye.

Open-angle glaucoma is any glaucoma in which the angle of the anteriorchamber remains open, but the exit of aqueous through the trabecularmeshwork is diminished. The exact cause for diminished filtration isunknown for most cases of open-angle glaucoma. Primary open-angleglaucoma is the most common of the glaucomas, and it is oftenasymptomatic in the early to moderately advanced stage. Patients maysuffer substantial, irreversible vision loss prior to diagnosis andtreatment. However, there are secondary open-angle glaucomas that mayinclude edema or swelling of the trabecular spaces (e.g., fromcorticosteroid use), abnormal pigment dispersion, or diseases such ashyperthyroidism that produce vascular congestion.

Current therapies for glaucoma are directed at decreasing intraocularpressure. Medical therapy includes topical ophthalmic drops or oralmedications that reduce the production or increase the outflow ofaqueous. However, these drug therapies for glaucoma are sometimesassociated with significant side effects, such as headache, blurredvision, allergic reactions, death from cardiopulmonary complications,and potential interactions with other drugs. When drug therapy fails,surgical therapy is used. Surgical therapy for open-angle glaucomaconsists of laser trabeculoplasty, trabeculectomy, and implantation ofaqueous shunts after failure of trabeculectomy or if trabeculectomy isunlikely to succeed. Trabeculectomy is a major surgery that is widelyused and is augmented with topically applied anticancer drugs, such as5-flurouracil or mitomycin-C to decrease scarring and increase thelikelihood of surgical success.

Approximately 100,000 trabeculectomies are performed on Medicare-agepatients per year in the United States. This number would likelyincrease if the morbidity associated with trabeculectomy could bedecreased. The current morbidity associated with trabeculectomy consistsof failure (10-15%); infection (a life long risk of 2-5%); choroidalhemorrhage, a severe internal hemorrhage from low intraocular pressure,resulting in visual loss (1%); cataract formation; and hypotonymaculopathy (potentially reversible visual loss from low intraocularpressure).

For these reasons, surgeons have tried for decades to develop a workablesurgery for the trabecular meshwork.

The surgical techniques that have been tried and practiced aregoniotomy/trabeculotomy and other mechanical disruptions of thetrabecular meshwork, such as trabeculopuncture, goniophotoablation,laser trabecular ablation, and goniocurretage. These are all majoroperations and are briefly described below.

Goniotomy/Trabeculotomy: Goniotomy and trabeculotomy are simple anddirected techniques of microsurgical dissection with mechanicaldisruption of the trabecular meshwork. These initially had earlyfavorable responses in the treatment of open-angle glaucoma. However,long-term review of surgical results showed only limited success inadults. In retrospect, these procedures probably failed due to cellularrepair and fibrosis mechanisms and a process of “filling in.” Filling inis a detrimental effect of collapsing and closing in of the openingcreated in the trabecular meshwork. Once the openings close, thepressure builds back up and the surgery fails.

Trabeculopuncture: Q-switched Neodymium (Nd) YAG lasers also have beeninvestigated as an optically invasive technique for creatingfull-thickness holes in trabecular meshwork. However, the relativelysmall hole created by this trabeculopuncture technique exhibits afilling-in effect and fails.

Goniophotoablation/Laser Trabecular Ablation: Goniophotoablation isdisclosed by Berlin in U.S. Pat. No. 4,846,172 and involves the use ofan excimer laser to treat glaucoma by ablating the trabecular meshwork.This was demonstrated not to succeed by clinical trial. Hill et al.disclosed the use of an Erbium:YAG laser to create full-thickness holesthrough trabecular meshwork (Hill et al., Lasers in Surgery and Medicine11:341-346, 1991). This technique was investigated in a primate modeland a limited human clinical trial at the University of California,Irvine. Although morbidity was zero in both trials, success rates didnot warrant further human trials. Failure was again from filling in ofsurgically created defects in the trabecular meshwork by repairmechanisms. Neither of these is a viable surgical technique for thetreatment of glaucoma.

Goniocurretage: This is an ab interno (from the inside), mechanicallydisruptive technique that uses an instrument similar to a cyclodialysisspatula with a microcurette at the tip. Initial results were similar totrabeculotomy: it failed due to repair mechanisms and a process offilling in.

Although trabeculectomy is the most commonly performed filteringsurgery, viscocanalostomy (VC) and non penetrating trabeculectomy (NPT)are two new variations of filtering surgery. These are ab externo (fromthe outside), major ocular procedures in which Schlemm's canal issurgically exposed by making a large and very deep scleral flap. In theVC procedure, Schlemm's canal is cannulated and viscoelastic substanceinjected (which dilates Schlemm's canal and the aqueous collectorchannels). In the NPT procedure, the inner wall of Schlemm's canal isstripped off after surgically exposing the canal.

Trabeculectomy, VC, and NPT involve the formation of an opening or holeunder the conjunctiva and scleral flap into the anterior chamber, suchthat aqueous humor is drained onto the surface of the eye or into thetissues located within the lateral wall of the eye. These surgicaloperations are major procedures with significant ocular morbidity. Wheretrabeculectomy, VC, and NPT were thought to have a low chance forsuccess in particular cases, a number of implantable drainage deviceshave been used to ensure that the desired filtration and outflow ofaqueous humor through the surgical opening will continue. The risk ofplacing a glaucoma drainage device also includes hemorrhage, infection,and diplopia (double vision).

All of the above surgeries and variations thereof have numerousdisadvantages and moderate success rates. They involve substantialtrauma to the eye and require great surgical skill in creating a holethrough the full thickness of the sclera into the subconjunctival space.The procedures are generally performed in an operating room and have aprolonged recovery time for vision.

The complications of existing filtration surgery have promptedophthalmic surgeons to find other approaches to lowering intraocularpressure or treating tissue of trabecular meshwork.

The trabecular meshwork and juxtacanalicular tissue together provide themajority of resistance to the outflow of aqueous and, as such, arelogical targets for tissue stimulation/rejuvenating or shunting in thetreatment of open-angle glaucoma. In addition, minimal amounts of tissueare displaced and functions of the existing physiologic outflow pathwaysare restored.

As reported in Arch. Ophthalm. (2000) 118:412, glaucoma remains aleading cause of blindness, and filtration surgery remains an effective,important option in controlling the disease. However, modifying existingfiltering surgery techniques in any profound way to increase theireffectiveness appears to have reached a dead end. The article furtherstates that the time has come to search for new surgical approaches thatmay provide better and safer care for patients with glaucoma.

Examples of implantable shunts and surgical methods for maintaining anopening for the release of aqueous from the anterior chamber of the eyeto the sclera or space beneath the conjunctiva have been disclosed in,for example, Hsia et al., U.S. Pat. No. 6,059,772 and Baerveldt, U.S.Pat. No. 6,050,970.

Examples of implantable shunts or devices for maintaining an opening forthe release of aqueous humor from the anterior chamber of the eye to thesclera or space underneath conjunctiva have been disclosed in U.S. Pat.No. 6,007,511 (Prywes), U.S. Pat. No. 6,007,510 (Nigam), U.S. Pat. No.5,893,837 (Eagles et al.), U.S. Pat. No. 5,882,327 (Jacob), U.S. Pat.No. 5,879,319 (Pynson et al.), U.S. Pat. No. 5,807,302 (Wandel), U.S.Pat. No. 5,752,928 (de Roulhac et al.), U.S. Pat. No. 5,743,868 (Brownet al.), U.S. Pat. No. 5,704,907 (Nordquist et al.), U.S. Pat. No.5,626,559 (Solomon), U.S. Pat. No. 5,626,558 (Suson), U.S. Pat. No.5,601,094 (Reiss), U.S. Pat. No. RE. 35,390 (Smith), U.S. Pat. No.5,558,630 (Fisher), U.S. Pat. No. 5,558,629 (Baerveldt et al.), U.S.Pat. No. 5,520,631 (Nordquist et al.), U.S. Pat. No. 5,476,445(Baerveldt et al.), U.S. Pat. No. 5,454,796 (Krupin), U.S. Pat. No.5,433,701 (Rubinstein), U.S. Pat. No. 5,397,300 (Baerveldt et al.), U.S.Pat. No. 5,372,577 (Ungerleider), U.S. Pat. No. 5,370,607 (Memmen), U.S.Pat. No. 5,338,291 (Speckman et al.), U.S. Pat. No. 5,300,020(L'Esperance, Jr.), U.S. Pat. No. 5,178,604 (Baerveldt et al.), U.S.Pat. No. 5,171,213 (Price, Jr.), U.S. Pat. No. 5,041,081 (Odrich), U.S.Pat. No. 4,968,296 (Ritch et al.), U.S. Pat. No. 4,936,825(Ungerleider), U.S. Pat. No. 4,886,488 (White), U.S. Pat. No. 4,750,901(Molteno), U.S. Pat. No. 4,634,418 (Binder), U.S. Pat. No. 4,604,087(Joseph), U.S. Pat. No. 4,554,918 (White), U.S. Pat. No. 4,521,210(Wong), U.S. Pat. No. 4,428,746 (Mendez), U.S. Pat. No. 4,402,681 (Haaset al.), U.S. Pat. No. 4,175,563 (Arenberg et al.), and U.S. Pat. No.4,037,604 (Newkirk).

All of the above embodiments and variations thereof have numerousdisadvantages and moderate success rates. They involve substantialtrauma to the eye and require great surgical skill in creating a holethrough the full thickness of the sclera into the subconjunctival space.The procedures are generally performed in an operating room and involvea prolonged recovery time for vision. The complications of existingfiltration surgery have prompted ophthalmic surgeons to find otherapproaches to lowering intraocular pressure.

Because the trabecular meshwork and juxtacanalicular tissue togetherprovide the majority of resistance to the outflow of aqueous, they arelogical targets for surgical removal in the treatment of open-angleglaucoma. In addition, minimal amounts of tissue need be altered andexisting physiologic outflow pathways can be utilized.

SUMMARY OF THE INVENTION

What is needed, therefore, is an extended, site-specific treatmentmethod for glaucoma that is faster, safer, and less expensive thancurrently available modalities. There is a great clinical need for animproved method of treating glaucoma that is faster, safer, and lessexpensive than currently available drug or surgical modalities. Themethods disclosed herein include ab interno and ab externo proceduresthat involve non-flap operations. The method herein may further compriseusing an innovative stenting device.

In accordance with some embodiments, a method of treating an oculardisorder is provided. The method involves introducing an implant into ananterior chamber of an eye. The implant is implanted into eye tissueadjacent the anterior chamber such that a proximal end of the implantresides in the anterior chamber following implantation. A therapeuticagent is eluted from the implant into the eye. Desirably, the release ofthe therapeutic agent from the implant is controlled. The controlledrelease of the therapeutic agent can be at a chosen rate and/or for aselected duration which can be episodic or periodic. The therapeuticagent can be an antiproliferative agent, an anti-inflammatory drug, or acompound for treating glaucoma or ocular hypertension.

In some preferred embodiments, the seton has an inlet portion configuredto extend through a portion of the trabecular meshwork of an eye, and anoutlet portion configured to extend into Schlemm's canal of the eye,wherein the inlet portion is disposed at an angle relative to the outletportion. In some embodiments, the outlet portion has a lumen with anoval cross-section having a long axis.

The outlet portion in certain embodiments has a longitudinal axis, suchthat the long axis of the oval cross-section and the longitudinal axisof the outlet portion define a plane, the inlet portion having alongitudinal axis that lies outside the plane at an angle θ (theta)thereto.

In some preferred arrangements, the seton comprises an inlet portion,configured to extend through a portion of the trabecular meshwork; anoutlet portion, configured to extend into Schlemm's canal; and at leastone protrusion on the outlet portion, configured to exert tractionagainst an inner surface of Schlemm's canal. This protrusion cancomprise at least one barb or ridge.

Some preferred embodiments comprise an inlet portion configured toextend through a portion of the trabecular meshwork, an outlet portionconfigured to extend into Schlemm's canal, and a one-way valve withinthe inlet and/or outlet portions.

A method for delivering a seton within an eye is disclosed, comprisingproviding an elongate guide member, advancing a distal end of the guidemember through at least a portion of the trabecular meshwork of the eye,advancing the seton along the guide member toward the distal end, andpositioning the seton to conduct aqueous humor between the anteriorchamber of the eye and Schlemm's canal.

In certain embodiments, the advancing of the guide member comprisesadvancing it from the anterior chamber into the trabecular meshwork. Infurther embodiments, the positioning comprises positioning an end of theseton within Schlemm's canal adjacent to an aqueous collection channel.

Certain preferred embodiments include an apparatus for delivering aseton to the anterior chamber of an eye comprising an elongate tubehaving a lumen, an outer surface, and a distal end; a removable,elongate guide member within the lumen, configured to permit the setonto be advanced and to be positioned in the trabecular meshwork of theeye. This apparatus can further comprise a cutting member positioned atthe distal end of the tube. The cutting member can be selected from thegroup consisting of a knife, a laser probe, a pointed guide member, asharpened distal end of said tube, and an ultrasonic cutter. Theapparatus can also further comprise an opening in the outer surface ofthe tube, configured to allow fluid infusion into the eye.

In further preferred embodiments, an apparatus for delivering a seton inan eye, comprises an elongate member adapted for insertion into ananterior chamber of the eye, the elongate member having a distal endportion configured to retain the seton therein, the distal end portioncomprising a cutting member configured to form an opening in thetrabecular meshwork of the eye for receipt of the seton, such that oneend of the seton is in Schlemm's canal. The elongate member can furthercomprise a lumen that conducts fluid toward said distal end portion.

The preferred embodiment provides further surgical treatment of glaucoma(trabecular bypass surgery) at the level of trabecular meshwork andrestores existing physiological outflow pathways. An implant bypassesdiseased trabecular meshwork at the level of trabecular meshwork andwhich restores existing physiological outflow pathways. The implant hasan inlet end, an outlet end and a lumen therebetween. The inlet ispositioned in the anterior chamber at the level of the internaltrabecular meshwork and the outlet end is positioned at about theexterior surface of the diseased trabecular meshwork and/or into fluidcollection channels of the existing outflow pathways.

In accordance with a preferred method, trabecular bypass surgery createsan opening or a hole through the diseased trabecular meshwork throughminor microsurgery. To prevent “filling in” of the hole, a biocompatibleelongated implant is placed within the hole as a seton, which mayinclude, for example, a solid rod or hollow tube. In one exemplaryembodiment, the seton implant may be positioned across the diseasedtrabecular meshwork alone and it does not extend into the eye wall orsclera. In another embodiment, the inlet end of the implant is exposedto the anterior chamber of the eye while the outlet end is positioned atthe exterior surface of the trabecular meshwork. In another exemplaryembodiment, the outlet end is positioned at and over the exteriorsurface of the trabecular meshwork and into the fluid collectionchannels of the existing outflow pathways. In still another embodiment,the outlet end is positioned in the Schlemm's canal. In an alternativeembodiment, the outlet end enters into fluid collection channels up tothe level of the aqueous veins with the seton inserted in a retrogradeor antegrade fashion.

According to the preferred embodiment, the seton implant is made ofbiocompatible material, which is either hollow to allow the flow ofaqueous humor or solid biocompatible material that imbibes aqueous. Thematerial for the seton may be selected from the group consisting ofporous material, semi-rigid material, soft material, hydrophilicmaterial, hydrophobic material, hydrogel, elastic material, and thelike.

In further accordance with the preferred embodiment, the seton implantmay be rigid or it may be made of relatively soft material and issomewhat curved at its distal section to fit into the existingphysiological outflow pathways, such as Schlemm's canal. The distalsection inside the outflow pathways may have an oval shape to stabilizethe seton in place without undue suturing. Stabilization or retention ofthe seton may be further strengthened by a taper end and/or by at leastone ridge or rib on the exterior surface of the distal section of theseton, or other surface alterations designed to retain the seton.

In one embodiment, the seton may include a micropump, one-way valve, orsemi-permeable membrane if reflux of red blood cells or serum proteinbecomes a clinical problem. It may also be useful to use a biocompatiblematerial that hydrates and expands after implantation so that the setonis locked into position around the trabecular meshwork opening or aroundthe distal section of the seton.

One of the advantages of trabecular bypass surgery, as disclosed herein,and the use of a seton implant to bypass diseased trabecular meshwork atthe level of trabecular meshwork and thereby use existing outflowpathways is that the treatment of glaucoma is substantially simpler thanin existing therapies. A further advantage of the invention is theutilization of simple microsurgery that may be performed on anoutpatient basis with rapid visual recovery and greatly decreasedmorbidity. Finally, a distinctly different approach is used than isfound in existing implants. Physiological outflow mechanisms are used orre-established by the implant of the present invention, incontradistinction with previously disclosed methodologies.

A device and method are provided for improved treatment of intraocularpressure due to glaucoma. A trabecular shunting and stenting device isadapted for implantation within a trabecular meshwork of an eye suchthat aqueous humor flows controllably from an anterior chamber of theeye to Schlemm's canal, bypassing the trabecular meshwork. Thetrabecular stenting device comprises a quantity of bioactive agentseffective in treating glaucoma, which are controllably released from thedevice into cells of the trabecular meshwork and/or Schlemm's canal.Depending upon the specific treatment contemplated, bioactive agents maybe utilized in conjunction with the trabecular stenting device such thataqueous flow either increases or decreases as desired. Placement of thetrabecular stenting device within the eye and incorporation, andeventual release, of a proven bioactive agents glaucoma therapy willreduce, inhibit or slow the effects of glaucoma.

One aspect of the invention provides a trabecular stenting device thatis implantable within an eye. The device comprises an inlet sectioncontaining at least one lumen, an outlet section having at least oneoutlet end. In one embodiment, there provides a flow-restricting memberwithin the lumen that is configured to prevent at least one component ofblood from passing through the flow-restricting member. In anotherembodiment, the device further comprises a middle section having atleast one lumen. The middle section is fixedly attached between theinlet section and the outlet section and the lumen is in fluidcommunication with the lumens of the inlet and outlet sections. Thedevice is configured to permit fluid entering the lumens of the inletsection, the middle section, and the outlet section, and then exit theoutlet section through the at least one outlet end.

Another aspect of the invention provides a method of treating glaucoma.The method comprises providing at least one bioactive agent or substanceincorporated into a trabecular stenting device, implanting thetrabecular stenting device within a trabecular meshwork of an eye suchthat a first end of the trabecular stent is positioned in an anteriorchamber of the eye while a second end is positioned in a Schlemm'scanal, and allowing the stenting device to release a quantity of thebioactive agent into the eye. The first and second ends of thetrabecular stenting device establish a fluid communication between theanterior chamber and the Schlemm's canal.

In another aspect of the invention, the bioactive agent comprises genes,growth factors, TGF-beta, scar inhibitors, and the like.

Still another aspect of the invention provides a method of regulatingintraocular pressure within an eye. The method comprises: providing atleast one bioactive agent incorporated into a trabecular stentingdevice; implanting the trabecular stenting device within a trabecularmeshwork of an eye such that a first end of the trabecular stent ispositioned in an anterior chamber of the eye while a second end ispositioned in a Schlemm's canal, wherein the first and second ends ofthe trabecular stenting device establish a fluid communication betweenthe anterior chamber and the Schlemm's canal; and allowing the stentingdevice to release a quantity of said bioactive agent into the eye.

Another aspect of the invention provides an apparatus for implanting atrabecular shunting/stenting device within an eye. The apparatuscomprises a syringe portion and a cannula portion that has proximal anddistal ends. The proximal end of the cannula portion is attached to thesyringe portion. The cannula portion further comprises a first lumen andat least one irrigating hole disposed between the proximal and distalends of the cannula portion. The irrigating hole is in fluidcommunication with the lumen. The apparatus further includes a holdercomprising a second lumen for holding the trabecular stenting device. Adistal end of the second lumen opens to the distal end of the cannulaportion, and a proximal end of the second lumen is separated from thefirst lumen of the cannula portion. The holder holds the trabecularstenting device during implantation of the device within the eye, andthe holder releases the trabecular stenting device when a practitioneractivates deployment of the device.

Another aspect of the invention provides a method of implanting atrabecular stenting device within an eye. The method comprises creatinga first incision in a cornea on a first side of the eye, wherein thefirst incision passes through the cornea into an anterior chamber of theeye. The method further comprises passing an incising device through thefirst incision and moving a distal end of the incising device across theanterior chamber to a trabecular meshwork residing on a second side ofthe eye, and using the incising device to create a second incision. Thesecond incision is in the trabecular meshwork, passing from the anteriorchamber through the trabecular meshwork into a Schlemm's canal. Themethod further comprises inserting the trabecular shunting/stentingdevice into a distal space of a delivery applicator. The method furthercomprises advancing the cannula portion having the trabecular stentingdevice through the first incision, across the anterior chamber and intothe second incision, wherein an outlet section of the trabecularstenting device is implanted into Schlemm's canal while an inlet sectionof the trabecular stenting device remains in fluid communication withthe anterior chamber. The method still further comprises releasing thetrabecular stenting device from the holder of the delivery applicator.

The trabecular meshwork and juxtacanalicular tissue together provide themajority of resistance to the outflow of aqueous and, as such, arelogical targets for the treatment of glaucoma. Various embodiments ofglaucoma devices and methods are disclosed herein for treating glaucomaby an ab interno procedure or an ab externo procedure, with respect totrabecular meshwork. The “ab interno” procedure is herein intended tomean any procedure that creates an opening from the anterior chamberthrough trabecular meshwork outwardly toward Schlemm's canal or towardscleral/cornea wall. This ab interno procedure may be initiated throughthe scleral wall or cornea wall into the anterior chamber as a firststep. The “ab externo” procedure is herein intended to mean anyprocedure that creates an opening on the scleral wall through trabecularmeshwork inwardly toward the anterior chamber. In most “ab externo”procedures disclosed herein, an instrument is passed through or contactsSchlemm's canal before entering trabecular meshwork and approaching theanterior chamber. The trabecular meshwork can generally be said to bebordered on one side by the anterior chamber and on the other side bySchlemm's canal.

Glaucoma surgical morbidity would greatly decrease if one were to bypassthe focal resistance to outflow of aqueous only at the point ofresistance, and to utilize remaining, healthy aqueous outflowmechanisms. This is in part because episcleral aqueous humor exerts abackpressure that prevents intraocular pressure from falling too low,and one could thereby avoid hypotony. Thus, such a surgery wouldvirtually eliminate the risk of hypotony-related maculopathy andchoroidal hemorrhage. Furthermore, visual recovery would be very rapid,and the risk of infection would be very small, reflecting a reduction inincidence from 2-5% to about 0.05%.

Copending U.S. application Ser. No. 09/549,350, filed Apr. 14, 2000,entitled APPARATUS AND METHOD FOR TREATING GLAUCOMA, and copending U.S.application Ser. No. 09/704,276, filed Nov. 1, 2000, entitled GLAUCOMATREATMENT DEVICE, disclose devices and methods of placing a trabecularshunt ab interno, i.e., from inside the anterior chamber through thetrabecular meshwork, into Schlemm's canal. The entire contents of eachone of these copending patent applications are hereby incorporated byreference herein. This application encompasses both ab interno and abexterno glaucoma shunts or stents and methods thereof.

One technique performed in accordance with certain aspects herein can bereferred to generally as “trabecular bypass surgery.” Advantages of thistype of surgery include lowering intraocular pressure in a manner thatis simple, effective, disease site-specific, and can potentially beperformed on an outpatient basis.

Generally, trabecular bypass surgery (TBS) creates an opening, a slit,or a hole through trabecular meshwork with minor microsurgery. TBS hasthe advantage of a much lower risk of choroidal hemorrhage and infectionthan prior techniques, and it uses existing physiologic outflowmechanisms. In some aspects, this surgery can potentially be performedunder topical or local anesthesia on an outpatient basis with rapidvisual recovery. To prevent “filling in” of the hole, a biocompatibleelongated hollow device is placed within the hole and serves as a stent.U.S. patent application Ser. No. 09/549,350, filed Apr. 14, 2000 and thecorresponding WO PCT US 01/07398 filed Mar. 8, 2001, the entire contentsof which are hereby incorporated by reference herein, disclosetrabecular bypass surgery in details.

As described in U.S. patent application Ser. No. 09/549,350, filed Apr.14, 2000, and U.S. application Ser. No. 09/704,276, filed Nov. 1, 2000,a trabecular shunt or stent for transporting aqueous humor is provided.The trabecular stent includes a hollow, elongate tubular element, havingan inlet section and an outlet section. The outlet section mayoptionally include two segments or elements, adapted to be positionedand stabilized inside Schlemm's canal. In one embodiment, the deviceappears as a “T” or an “L” shaped device.

In accordance with one aspect of at least one of the inventionsdisclosed herein, a delivery apparatus (or “applicator”) is used forplacing a trabecular stent through a trabecular meshwork of an eye.Certain embodiments of such a delivery apparatus are disclosed incopending U.S. application Ser. No. 10/101,548, filed Mar. 18, 2002,entitled APPLICATOR AND METHODS FOR PLACING A TRABECULAR SHUNT FORGLAUCOMA TREATMENT, and U.S. Provisional Application No. 60/276,609,filed Mar. 16, 2001, entitled APPLICATOR AND METHODS FOR PLACING ATRABECULAR SHUNT FOR GLAUCOMA TREATMENT, the entire contents of each oneof which are hereby incorporated by reference herein.

The stent has an inlet section and an outlet section. The deliveryapparatus includes a handpiece, an elongate tip, a holder and anactuator. The handpiece has a distal end and a proximal end. Theelongate tip is connected to the distal end of the handpiece. Theelongate tip has a distal portion and is configured to be placed througha corneal incision and into an anterior chamber of the eye. The holderis attached to the distal portion of the elongate tip. The holder isconfigured to hold and release the inlet section of the trabecularstent. The actuator is on the handpiece and actuates the holder torelease the inlet section of the trabecular stent from the holder. Whenthe trabecular stent is deployed from the delivery apparatus into theeye, the outlet section is positioned in substantially oppositedirections inside Schlemm's canal. In one embodiment, a deploymentmechanism within the delivery apparatus includes a push-pull typeplunger.

Some aspects of at least one of the inventions disclosed herein relateto devices for reducing intraocular pressure by providing outflow ofaqueous from an anterior chamber of an eye. The device generallycomprises an elongated tubular member and cutting means. The tubularmember is adapted for extending through a trabecular meshwork of theeye. The tubular member generally comprises a lumen having an inlet portand at least one outlet port for providing a flow pathway. The cuttingmeans is mechanically connected to or is an integral part of the tubularmember for creating an incision in the trabecular meshwork for receivingat least a portion of the tubular member.

In one embodiment, a self-trephining glaucoma stent is provided forreducing and/or balancing intraocular pressure in an eye. The stentgenerally comprises a snorkel and a curved blade. The snorkel generallycomprises an upper seat for stabilizing said stent within the eye, ashank and a lumen. The shank is mechanically connected to the seat andis adapted for extending through a trabecular meshwork of the eye. Thelumen extends through the snorkel and has at least one inlet flow portand at least one outlet flow port. The blade is mechanically connectedto the snorkel. The blade generally comprises a cutting tip proximate adistal-most point of the blade for making an incision in the trabecularmeshwork for receiving the shank.

Some aspects of at least one of the inventions disclosed herein relateto methods of implanting a trabecular stent device in an eye. In oneembodiment, the device has a snorkel mechanically connected to a blade.The blade is advanced through a trabecular meshwork of the eye to cutthe trabecular meshwork and form an incision therein. At least a portionof the snorkel is inserted in the incision to implant the device in theeye.

Some aspects provide a self-trephining glaucoma stent and methodsthereof, which advantageously allow for a “one-step” procedure in whichthe incision and placement of the stent are accomplished by a singledevice and operation. This desirably allows for a faster, safer, andless expensive surgical procedure. In any of the embodiments, fiducialmarkings, indicia, or the like and/or positioning of the stent device ina preloaded applicator may be used for proper orientation and alignmentof the device during implantation.

Among the advantages of trabecular bypass surgery is its simplicity. Themicrosurgery may potentially be performed on an outpatient basis withrapid visual recovery and greatly decreased morbidity. There is a lowerrisk of infection and choroidal hemorrhage, and there is a fasterrecovery, than with previous techniques.

Some aspects of at least one of the inventions disclosed herein relateto a medical device system for treating glaucoma of an eye comprisingusing OCT (optical coherence tomography) as an imaging and locatingsystem for trabecular stent placement. In one embodiment, the procedurewould first be set up with triangulation or some means to reliablyestablish the implant location in x, y, and z coordinates by using OCTwithin a few microns, most preferably in a non-invasive, non-contactmanner. Having acquired the target space or location, the trabecularstent device would then be injected into place either via an ab internoprocedure or an ab externo procedure. An article by Hoerauf et al.(Graefe's Arch Clin Exp Ophthalmol 2000; 238:8-18 published bySpringer-Verlag), entire contents of which are incorporated herein byreference, discloses a slit-lamp adapted optical coherence tomography ofthe anterior segment.

Some aspects of at least one of the inventions disclosed herein relateto a ‘foldable’ stent wherein the size of the stent is reduced in orderto place it through a yet smaller ocular entrance wound, as small ashalf or less than the size of the unfolded stent. The smallest sizewound is important to aid in recovery, to prevent complications, and tominimize the preparation and extent of the surgical environment. Inanother embodiment, the device is positioned through the trabecularmeshwork in an ab externo or ab interno procedure. Reliablevisualization (OCT, UBM, gonioscope, electromagnetic or other means) isa key enabler for micro precision surgery such as a trabecular bypasssurgery using a microstent.

Some aspects of at least one of the inventions disclosed herein relateto a medical device system with trephining capability, wherein a cuttingmechanism is on or as part of the applicator for purposes of making thehole in trabecular meshwork for stent insertion. In one aspect, acutting tip may protrude through the lumen of the stent. In another, thetip extends down the side of the snorkel without entering the lumen. Instill another, the tip either passes through the lumen or down the sideand further extends to the tip of the stent that is the leading edgeduring insertion. In one embodiment, the cutting tip can be designed toretract after making the incision but before insertion of the stent intoSchlemm's canal if it interferes with the insertion operation. It couldalso be retracted after insertion of the stent into Schlemm's canal.

Some aspects of at least one of the inventions disclosed herein providean implant for treating glaucoma, the implant having a longitudinalimplant axis, and comprising an outflow portion through which a portionof the longitudinal implant axis passes, the outflow portion shaped andsized to be (a) introduced into Schlemm's canal with the portion of thelongitudinal implant axis at an angle to Schlemm's canal; and (b)received with Schlemm's canal regardless of the rotational orientationof the outflow portion about the portion of the longitudinal implantaxis during the introduction; and an inflow portion in fluidcommunication with the outflow portion, the inflow portion configured topermit communication of fluid from the anterior chamber of the eye tothe outflow portion.

Some aspects of at least one of the inventions disclosed herein providean implant for treating glaucoma, comprising: an outflow portion, sizedand shaped to be received within Schlemm's canal, the outflow portioncomprising: an outflow portion base having an outflow opening and atleast one standoff member disposed to space the outflow opening from awall of Schlemm's canal, such that the opening is unobstructed by thecanal wall.

Some aspects of at least one of the inventions disclosed herein providean implant for treating glaucoma, the implant having a longitudinalimplant axis and comprising: a first portion at a first end of thelongitudinal implant axis, the first portion sized and configured toreside in Schlemm's canal, such that the first portion has a maximumdimension along a longitudinal axis of Schlemm's canal that is notsubstantially greater than a dimension of the first portion that runsperpendicular to both the longitudinal axis of Schlemm's canal and tothe longitudinal implant axis; and a second portion at a second end ofthe longitudinal implant axis, the second portion configured to providefluid communication between the anterior chamber and the first portion.

Some aspects of at least one of the inventions disclosed herein providean implant for treating glaucoma, comprising: an outflow portion, sizedand shaped to be received within Schlemm's canal; an inflow portion influid communication with the outflow portion, the inflow portionconfigured to be disposed in the anterior chamber of the eye; and acentral portion extending between the inflow and outflow portions; theoutflow portion having a diameter that is no more than three times thediameter of the central portion.

In accordance with one embodiment of at least one of the inventionsdisclosed herein, an implant for treating glaucoma is provided. Theimplant includes a longitudinal implant axis, and comprises an outflowportion through which said longitudinal implant axis passes. The outflowportion is shaped and sized to be introduced into Schlemm's canal withthe portion of the longitudinal implant axis at an angle to Schlemm'scanal. The outflow portion is also shaped and sized to be receivedwithin Schlemm's canal regardless of a rotational orientation of theoutflow portion about said longitudinal implant axis during saidintroduction. The implant also comprises an inflow portion configured topermit communication of fluid from the anterior chamber of the eye tothe outflow portion.

In accordance with another embodiment of at least one of the inventionsdisclosed herein, an implant for treating glaucoma is provided. Theimplant comprises an outflow portion, sized and shaped to be receivedwithin Schlemm's canal. The outflow portion comprises an outflow portionbase having an outflow opening and at least one standoff member disposedto space said outflow opening from a wall of Schlemm's canal, such thatsaid outflow opening is unobstructed by said canal wall.

In accordance with a further embodiment of at least one of theinventions disclosed herein, an implant for treating glaucoma isprovided. The implant includes a longitudinal implant axis and comprisesa first portion at a first end of said longitudinal implant axis. Thefirst portion is sized and configured to reside in Schlemm's canal, suchthat said first portion has a maximum dimension along a longitudinalaxis of Schlemm's canal that is not substantially greater than adimension of the first portion that runs perpendicular to both saidlongitudinal axis of Schlemm's canal and to said longitudinal implantaxis. A second portion at a second end of said longitudinal implant axisis configured to provide fluid communication between the anteriorchamber and said first portion.

In accordance with yet another embodiment of at least one of theinventions disclosed herein, an implant for treating glaucoma comprisesan outflow portion, sized and shaped to be received within Schlemm'scanal. An inflow portion is in fluid communication with said outflowportion, the inflow portion configured to be disposed in the anteriorchamber of the eye. A central portion extending between the inflow andoutflow portions. The outflow portion having a diameter that is no morethan three times the diameter of the central portion.

In accordance with yet another embodiment of at least one of theinventions disclosed herein, an instrument for delivering implants fortreating an ophthalmic condition is provided. The instrument comprisesan elongate body sized to be introduced into an eye through an incisionin the eye. A plurality of implants is positioned in the elongate body.The elongate body further comprises an actuator that serially dispensesthe implants from the elongate body for implanting in eye tissue.

In accordance with another embodiment of at least one of the inventionsdisclosed herein, a method of implanting a plurality of implants fortreating glaucoma is provided. The method includes inserting aninstrument into an eye through an incision, utilizing the instrument todeliver a first implant through a wall of Schlemm's canal at a firstlocation, and utilizing the instrument to deliver a second implantthrough a wall of Schlemm's canal at a second location, without removingthe instrument from the eye between the deliveries of said implants.

In accordance with yet another embodiment of at least one of theinventions disclosed herein, a method of implanting a plurality ofimplants for treating glaucoma is provided. The method includesinserting an instrument into an eye through an incision, utilizing theinstrument to deliver a first implant through a wall of Schlemm's canalat a first location, and utilizing the instrument to deliver a secondimplant through a wall of Schlemm's canal at a second location, whereinthe locations are determined from morphological data on collectorchannel locations.

In accordance with yet another embodiment of at least one of theinventions disclosed herein, a method of implanting a plurality ofimplants for treating glaucoma is provided. The method comprisesinserting an instrument into an eye through an incision, utilizing theinstrument to deliver a first implant through a wall of Schlemm's canalat a first location, and utilizing said instrument to deliver a secondimplant through a wall of Schlemm's canal at a second location. Thelocations are determined by imaging collector channel locations.

In accordance with a further embodiment of at least one of theinventions disclosed herein, a method of implanting a plurality ofimplants for treating glaucoma is provided. The method comprisesinserting an instrument into an eye through an incision, utilizing theinstrument to deliver a first implant through a wall of Schlemm's canalat a first location, and utilizing said instrument to deliver a secondimplant through a wall of Schlemm's canal at a second location. Thelocations are angularly spaced along Schlemm's canal by at least 20degrees.

In accordance with yet another embodiment of at least one of theinventions disclosed herein, a method of implanting a plurality ofimplants for treating glaucoma is provided. The method comprisesinserting an instrument into an eye through an incision, utilizing theinstrument to deliver a first implant through a wall of Schlemm's canalat a first location, utilizing the instrument to deliver a secondimplant through a wall of Schlemm's canal at a second location. Thefirst and second locations are substantially at collector channels.

In accordance with another embodiment of at least one of the inventionsdisclosed herein, a method of implanting a plurality of implants fortreating glaucoma is provided. The method comprises inserting aninstrument into an eye through an incision, utilizing the instrument todeliver a first implant through a wall of Schlemm's canal at a firstlocation, and utilizing said instrument to deliver a second implantthrough a wall of Schlemm's canal at a second location. The implantshave different flow characteristics.

In accordance with yet another embodiment of at least one of theinventions disclosed herein, a method of implanting a plurality ofimplants for treating glaucoma is provided. The method comprisesinserting an instrument into an eye through an incision, utilizing theinstrument to deliver a first implant into the posterior segment of theeye, and utilizing the instrument to deliver a second implant into theposterior segment of the eye at a second location. The instrument is notremoved from the eye between said deliveries of the implants.

In accordance with a further embodiment of at least one of theinventions disclosed herein, a method of implanting a plurality ofimplants for treating glaucoma is provided. The method comprisesserially dispensing a plurality of preloaded implants from an instrumentinto eye tissue at a respective plurality of locations within the eye.

For purposes of summarizing, certain aspects, advantages and novelfeatures of the inventions disclosed herein have been described hereinabove. Of course, it is to be understood that not necessarily all suchadvantages may be achieved in accordance with any particular embodiment.Thus, the inventions may be embodied or carried out in a manner thatachieves or optimizes one advantage or group of advantages as taught orsuggested herein without necessarily achieving other advantages as maybe taught or suggested herein.

Some embodiments include an implant for treating glaucoma, comprising abody comprising material that includes a drug, the body having an inletportion and an outlet portion, the inlet portion configured to transportfluid from the anterior chamber of an eye to the outlet portion when theoutlet portion is disposed in Schlemm's canal of the eye, the outletportion having an outflow opening.

In some embodiments, the body is coated with the drug. In someembodiments, the drug comprises heparin.

Some embodiments include an implant for treating glaucoma, comprising abody having a bioactive agent in or on the body, the body having aninlet portion and an outlet portion, the inlet portion configured totransmit fluid from the anterior chamber to the outlet portion when theoutlet portion is disposed in Schlemm's canal, the outlet portion havingan outflow opening.

In some embodiments, the bioactive agent comprises TGF-beta, a gene, ananti-inflammatory drug, and/or an intraocular pressure-lowering drug.

In some embodiments, the bioactive agent comprises a growth factorand/or an antiproliferative agent.

In some embodiments, the bioactive agent is loaded onto a surface of theoutlet section.

Some embodiments further comprise a biodegradable material in or on theimplant. In some embodiments, the biodegradable material is selectedfrom the group consisting of poly(lactic acid), polyethylene-vinylacetate, poly(lactic-co-glycolic acid), poly(D,L-lactide),poly(D,L-lactide-co-trimethylene carbonate), collagen, heparinizedcollagen, poly(caprolactone), poly(glycolic acid), and a copolymer.

In some embodiments, the outlet end further comprises a plurality ofpillars at the outlet end. In some embodiments, the bioactive agent isin or on at least one of the pillars.

In some embodiments, the implant is at least partially coated with atleast one polymer film that contains the bioactive agent, the polymerfilm permitting a delivery of a quantity of the bioactive agent toocular tissues over time.

Some embodiments include an ocular implant comprising a body having abioactive agent in or on the body, the body further comprising an inletsection configured to be positioned in the anterior chamber of an eye;an outlet section configured to be positioned at least partially inSchlemm's canal of the eye, the outlet section being in fluidcommunication with the inlet section; a lumen extending between theinlet section and the outlet section; and a flow-restricting memberwithin the lumen, the flow-restricting member being configured toprevent at least one component of blood from passing through theflow-restricting member.

In some embodiments, the bioactive agent comprises an Imidazoleantiproliferative agent, a quinoxaline, a phosphonylmethoxyalkylnucleotide analog, a potassium channel blocker, and/or a syntheticoligonucleotide. In some embodiments, the bioactive agent comprises5-[1-hydroxy-2-[2-(2-methoxyphenoxyl) ethylamino]ethyl]-2-methylbenzenesulfonamide.

In some embodiments, the bioactive agent comprises a guanylate cyclaseinhibitor, such as methylene blue, butylated hydroxyanisole, and/orN-methylhydroxylamine. In some embodiments, the bioactive agentcomprises 2-(4-methylaminobutoxy) diphenylmethane. In some embodiments,the bioactive agent comprises a combination of apraclonidine andtimolol.

In some embodiments, the bioactive agent comprises a cloprostenol analogor a fluprostenol analog. In some embodiments, the bioactive agentcomprises a crosslinked carboxy-containing polymer, a sugar, and water.In some embodiments, the bioactive agent comprises a non-corneotoxicserine-threonine kinase inhibitor. In some embodiments, the bioactiveagent comprises a nonsteroidal glucocorticoid antagonist. In someembodiments, the bioactive agent comprises a prostaglandin analog or aderivative thereof.

These and other embodiments of the inventions will become apparent tothose skilled in the art from the following detailed description ofexemplary embodiments having reference to the attached figures, theinventions not being limited to any particular preferred embodiment(s)disclosed.

BRIEF DESCRIPTION OF THE DRAWINGS

Certain preferred embodiments and modifications thereof will becomeapparent to those skilled in the art from the detailed descriptionherein having reference to the figures that follow, of which:

FIG. 1 is a coronal cross-sectional view of an eye.

FIG. 2 is an enlarged cross-sectional view of an anterior chamber angleof the eye of FIG. 1 with a trabecular stent.

FIG. 3 is a schematic and partial sectional view of an eye illustratingan implanted glaucoma stent in accordance with one embodiment of atleast one of the inventions disclosed herein.

FIG. 4 is a side elevational view of the stent of FIG. 3.

FIG. 5 is a top plan view of the stent of FIG. 3.

FIG. 6 is a bottom plan view of the stent of FIG. 3.

FIG. 7 is a front elevational view of the stent of FIG. 3 (along line7-7 of FIG. 4).

FIG. 8 is a rear elevational view of the stent of FIG. 3 (along line 8-8of FIG. 4).

FIG. 9 is an enlarged top plan view of a forward end of the stent ofFIG. 3.

FIG. 10 is a top plan view of a modification of an inlet end of thestent of FIG. 3.

FIG. 11 is a top plan view of another modification of the inlet end ofthe stent of FIG. 3.

FIG. 12 is a top plan view of yet another modification of the inlet endof the stent of FIG. 3.

FIG. 13 is a top plan view of still another modification of the inletend of the stent of FIG. 3.

FIG. 14 is schematic and partial sectional view of an eye illustrating amodification of the implanted glaucoma stent of FIG. 3.

FIG. 15 is a schematic and partial sectional view of an eye illustratinga further modification of the implanted glaucoma stent of FIG. 3.

FIG. 16 is a side elevational view of yet another modification of theglaucoma stent of FIG. 3.

FIG. 17 is a top plan view of the stent of FIG. 16.

FIG. 18 is a bottom plan view of the stent of FIG. 16.

FIG. 19 is a front elevational view along line 19-19 of FIG. 16.

FIG. 20 is a rear elevational view along line 20-20 of FIG. 16.

FIG. 21 is a side elevation view of still another modification of theglaucoma stent of FIG. 3.

FIG. 22 is a top plan view of the stent of FIG. 21.

FIG. 23 is a bottom plan view of the stent of FIG. 21.

FIG. 24 is a front elevational view along line 24-24 of FIG. 21.

FIG. 25 is a rear elevational view along line 25-25 of FIG. 21.

FIG. 26 is a front elevational view of a modification of the glaucomastent illustrated in FIG. 3.

FIG. 27 is a right side elevational view of the stents illustrated inFIG. 26 as viewed along the line 27-27.

FIG. 28 is a right side elevational view of the glaucoma stentillustrated in FIG. 26, as viewed along the line 28-28.

FIG. 29 is a schematic and partial sectional view of an eye illustratinga temporal implantation of a glaucoma stent using a delivery apparatushaving features and advantages in accordance with at least one of theinventions disclosed herein.

FIG. 30 is an oblique elevational view of an articulating arm stentdelivery/retrieval apparatus having features and advantages inaccordance with an embodiment of at least one of the inventionsdisclosed herein.

FIG. 31 is a schematic and partial sectional view of a portion of an eyeand illustrating an implantation of a glaucoma stent using a deliveryapparatus extending through the anterior chamber of the eye.

FIG. 32 is a schematic and partial sectional view of a Schlemm's canaland trabecular meshwork of an eye with another glaucoma stent extendingfrom the anterior chamber of the eye, through the trabecular meshwork,and into a rear wall of the Schlemm's canal.

FIG. 33 is an enlarged cross-sectional view of a distal portion of thestent illustrated in FIG. 32.

FIG. 34 is a schematic and partial sectional view of the eye of FIG. 32and a side elevational view of a modification of the stent illustratedin FIG. 32.

FIG. 35 is a schematic and partial sectional view of the eye illustratedin FIG. 32, and a side elevational view of a photomodification of thestent illustrated in FIG. 32.

FIG. 36 is a schematic and partial sectional view of the eye illustratedin FIG. 32, and a side elevational view of another modification of thestent of FIG. 32.

FIG. 37 is a schematic and partial sectional view of the eye illustratedin FIG. 32, and a side elevational view of a further modification of theimplant illustrated in FIG. 32.

FIG. 38 is a schematic and partial sectional view of the eye illustratedin FIG. 32 and a side elevational view of another modification of thestent illustrated in FIG. 32.

FIG. 39 is a schematic and partial sectional view of the eye illustratedin FIG. 32, and a side elevational view of the further modification ofthe implant illustrated in FIG. 32.

FIG. 40 is a schematic and partial sectional view of the eye illustratedin FIG. 32, and a side elevational view of yet another modification ofthe stent illustrated in FIG. 32.

FIG. 41 is a schematic and partial sectional view of an eye and the sideelevational view of yet another modification of the stent illustrated inFIG. 32.

FIG. 42 is a schematic and partial sectional view of the eye illustratedin FIG. 32, and a side elevational view of yet another modification ofthe implant illustrated in FIG. 32.

FIG. 43 is an enlarged schematic and partial cross-sectional view of ananterior chamber angle of an eye having a valve stent implanted therein.

FIG. 44 is an enlarged cross-sectional view of an anterior chamber angleof an eye including an osmotic membrane device implanted therein.

FIG. 45 is an enlarged cross-sectional view of an anterior chamber angleof an eye illustrating an implantation of a glaucoma stent using an abexterno procedure.

FIG. 46 is a schematic and partial sectional view of the eye illustratedin FIG. 32 and a side elevational view of another modification of theimplant illustrated in FIG. 32.

FIG. 47 is an enlarged schematic and partial sectional view of the eyeillustrated in FIG. 32 and including a drug release device implantedtherein.

FIG. 48 is a flow diagram illustrating a method for treating glaucoma.

FIG. 49A is an enlarged schematic illustration showing an anteriorchamber, trabecular meshwork and a Schlemm's canal of an eye and anoblique elevational view of yet another modification of the stentillustrated in FIG. 32.

FIG. 49B is an oblique elevational view of a modification of the stentillustrated in FIG. 49A.

FIG. 49C is a side elevational view of another modification of the stentillustrated in FIG. 49A.

FIG. 50A is a cross-sectional view of the eye portion showinganatomically the trabecular meshwork, Schlemm's canal and one collectorduct.

FIG. 50B is a cross-sectional view of FIG. 50A with a portion of a stentmechanically inserted into one of the collector ducts.

FIG. 51A is a side elevational view of a stent delivery applicator witha steerable distal section for multiple stent deployment.

FIG. 51B is a schematic and partial sectional view of the distal sectionof the stent delivery applicator of FIG. 51A.

FIG. 51C is a cross-sectional view, section 1-1 of FIG. 51B.

FIG. 51D is an oblique side elevational view of the steerable section ofthe delivery applicator illustrated in FIG. 51A and including anoptional ultrasonically enabled distal end.

FIG. 52A is a partial sectional and side elevational view of a distalsection of a modification of the stent delivery applicator illustratedin FIG. 51A.

FIG. 52B is a partial sectional and side elevational view of a distalsection of the stent delivery applicator illustrated in FIG. 51A havingbeen inserted through a trabecular meshwork with the stent disposedwithin the distal section.

FIG. 52C is a partial sectional and side elevational view of a distalsection of the stent delivery applicator illustrated in FIG. 51A havingbeen inserted through a trabecular meshwork and after the sheath of thedistal portion has been withdrawn.

FIG. 52D is a partial sectional and side elevational view of a distalsection of the stent delivery applicator illustrated in FIG. 51A havingbeen inserted through a trabecular meshwork, and after the sheath and acutting member have been withdrawn.

FIG. 53 is an oblique side elevational and partial sectional view of afurther modification of the stent illustrated in FIG. 32.

FIG. 54A is a sectional view of yet another modification of the stentdelivery applicator illustrated in FIG. 51A.

FIG. 54B is an enlarged sectional view of a distal end of the applicatorillustrated in FIG. 54A and including two implants disposed over atrocar of the device, this portion being identified by the circle 2-2 inFIG. 54A.

FIG. 54C is a sectional view of the applicator device taken alongsection line 3-3 of FIG. 54A.

FIG. 55 shows an embodiment of a seton implant constructed according tothe principles of the invention.

FIG. 56 is a top cross-sectional view of section 1-1 of FIG. 55.

FIG. 57 is another embodiment of a seton implant constructed inaccordance with the principles of the invention.

FIG. 58 is an oblique elevation view of one embodiment of a trabecularstenting device.

FIG. 59 is an oblique elevation view of another embodiment of atrabecular stenting device.

FIG. 60 is an oblique elevation view of placement of one end of atrabecular stenting device through a trabecular meshwork.

FIG. 61 is an oblique elevation view of placement of one end of atrabecular stenting device through a trabecular meshwork, wherein thetrabecular stenting device is passed over a guidewire.

FIG. 62 is an oblique elevation view of a preferred implantation of atrabecular stenting device through a trabecular meshwork.

FIG. 63 is a close-up, cut-away view of an inlet section of thetrabecular stenting device of FIGS. 58 and 59, illustrating aflow-restricting member retained within a lumen of the trabecularstenting device.

FIG. 64 is one embodiment of an axisymmetric trabecular stenting devicefor incorporating bioactive agents.

FIG. 65 is one embodiment of a fistula without a lumen for transportingaqueous and carrying bioactive agents of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The preferred embodiments described herein relate particularly tosurgical and therapeutic treatment of glaucoma through reduction ofintraocular pressure and/or stimulation of the trabecular meshworktissue. While the description sets forth various embodiment-specificdetails, it will be appreciated that the description is illustrativeonly and should not be construed in any way as limiting the invention.Furthermore, various applications of the inventions disclosed herein,and modifications thereto, which may occur to those who are skilled inthe art, are also encompassed by the general concepts described herein.

FIG. 1 is a cross-sectional view of an eye 10. FIG. 2 is an enlargedsectional view of the eye showing the relative anatomical locations of atrabecular meshwork 21, an anterior chamber 20, and a Schlemm's canal22. A sclera 11 is a thick collagenous tissue that covers the entire eye10 except a portion that is covered by a cornea 12.

With reference to FIGS. 1 and 2, the cornea 12 is a thin transparenttissue that focuses and transmits light into the eye and through a pupil14, which is a circular hole in the center of an iris 13 (coloredportion of the eye). The cornea 12 merges into the sclera 11 at ajuncture referred to as a limbus 15. A ciliary body 16 extends along theinterior of the sclera 11 and is coextensive with a choroid 17. Thechoroid 17 is a vascular layer of the eye 10, located between the sclera11 and a retina 18. An optic nerve 19 transmits visual information tothe brain and is the anatomic structure that is progressively destroyedby glaucoma.

With continued reference to FIGS. 1 and 2, the anterior chamber 20 ofthe eye 10, which is bound anteriorly by the cornea 12 and posteriorlyby the iris 13 and a lens 26, is filled with aqueous humor (hereinafterreferred to as “aqueous”). Aqueous is produced primarily by the ciliarybody 16, then moves anteriorly through the pupil 14 and reaches ananterior chamber angle 25, formed between the iris 13 and the cornea 12.

As best illustrated by the drawing of FIG. 2, in a normal eye, aqueousis removed from the anterior chamber 20 through the trabecular meshwork21. Aqueous passes through the trabecular meshwork 21 into Schlemm'scanal 22 and thereafter through a plurality of collector ducts andaqueous veins 23, which merge with blood-carrying veins, and intosystemic venous circulation. Intraocular pressure is maintained by anintricate balance between secretion and outflow of aqueous in the mannerdescribed above. Glaucoma is, in most cases, characterized by anexcessive buildup of aqueous in the anterior chamber 20, which leads toan increase in intraocular pressure. Fluids are relativelyincompressible, and thus intraocular pressure is distributed relativelyuniformly throughout the eye 10.

As shown in FIG. 2, the trabecular meshwork 21 is adjacent a smallportion of the sclera 11. Exterior to the sclera 11 is a conjunctiva 24.Traditional procedures that create a hole or opening for implanting adevice through the tissues of the conjunctiva 24 and sclera 11 involveextensive surgery, as compared to surgery for implanting a device, asdescribed herein, which ultimately resides entirely within the confinesof the sclera 11 and cornea 12. A trabecular stent 229 can be placedbypassing the trabecular meshwork 21 with a proximal terminal 227exposed to anterior chamber 20 and a distal terminal 228 exposed toSchlemm's canal 22.

FIG. 3 schematically illustrates the use of one embodiment of atrabecular stenting device 30 for establishing an outflow pathway,passing through the trabecular meshwork 21, described in greater detailbelow. FIGS. 4-9 are different views of the stent 30. Advantageously,and as discussed in further detail later herein, theself-trephining-stent allows a one-step procedure to make an incision inthe trabecular mesh 21 and place the stent or implant 30 at the desiredor predetermined position within the eye 10. Desirably, this facilitatesand simplifies the overall surgical procedure.

In the illustrated embodiment of FIGS. 3-9, the shunt or stent 30generally comprises an inlet portion or “snorkel” 32 and a main bodyportion or blade 34. The snorkel 32 and blade 34 are mechanicallyconnected to or in mechanical communication with one another. Agenerally longitudinal axis 36 extends along the stent 30 and/or thebody portion 34.

In the illustrated embodiment of FIGS. 3-9, the stent 30 comprises anintegral unit. In modified embodiments, the stent 30 may comprise anassembly of individual pieces or components. For example, the stent 30may comprise an assembly of the snorkel 32 and blade 34.

In the illustrated embodiment of FIGS. 3-9, the snorkel 32 is in theform of a generally elongate tubular member and generally comprises anupper seat, head or cap portion 38, a shank portion 40 and a lumen orpassage 42 extending therethrough. The seat 38 is mechanically connectedto or in mechanical communication with the shank 40, which is alsomechanically connected to, or in mechanical communication with the blade34. The longitudinal axis 43 extends along the snorkel 32 and/or thelumen 42.

In the illustrated embodiment of FIGS. 3-9, the seat 38 is generallycircular in shape and has an upper surface 44 and a lower surface 46,which, as shown in FIG. 3, abuts or rests against the trabecularmeshwork 21 to stabilize the glaucoma stent 30 within the eye 10. Inmodified embodiments, the seat 38 may efficaciously be shaped in othersuitable manners, as required or desired, giving due consideration tothe goals of stabilizing the glaucoma stent 30 within the eye 10 and/orof achieving one or more of the benefits and advantages as taught orsuggested herein. For example, the seat 38 may be shaped in otherpolygonal or non-polygonal shapes and/or comprise one or more ridgeswhich extend radially outwards, among other suitable retention devices.

In the illustrated embodiment of FIGS. 3-9, and as best seen in the topview of FIG. 5, the seat top surface 44 comprises fiducial marks orindicia 48. These marks or indicia 48 facilitate and ensure properorientation and alignment of the stent 30 when implanted in the eye 10.The marks or indicia 48 may comprise visual differentiation means suchas color contrast or be in the form of ribs, grooves, or the like.Alternatively, or in addition, the marks 48 may provide tactile sensoryfeedback to the surgeon by incorporating a radiopaque detectable orultrasound imaginable substrate at about the mark 48. Also, the seat 38and/or the seat top surface 44 may be configured in predetermined shapesaligned with the blade 34 and/or longitudinal axis 36 to provide forproper orientation of the stent device 30 within the eye 10. Forexample, the seat top surface 44 may be oval or ellipsoidal (FIG. 10),rectangular (FIG. 11), hexagonal (FIG. 12), among other suitable shapes(e.g. FIG. 13).

In the illustrated embodiment of FIGS. 3-9, and as indicated above, theseat bottom surface 46 abuts or rests against the trabecular meshwork 21to stabilize and retain the glaucoma stent 30 within the eye 10. Forstabilization purposes, the seat bottom surface 46 may comprise astudded surface, a ribbed surface, a surface with pillars, a texturedsurface, or the like.

In the illustrated embodiment of FIGS. 3-9, the snorkel shank 40 isgenerally cylindrical in shape. With the stent 30 implanted, as shown inFIG. 3, the shank 40 is generally positioned in an incision or cavity 50formed in the trabecular meshwork 21 by the self-trephining stent 30.Advantageously, and as discussed further below, this single step offorming the cavity 50 by the stent 30 itself and placing the stent 30 inthe desired position facilitates and expedites the overall surgicalprocedure. In modified embodiments, the snorkel shank 40 mayefficaciously be shaped in other suitable manners, as required ordesired. For example, the shank 40 may be in the shape of otherpolygonal or non-polygonal shapes, such as, oval, ellipsoidal, and thelike.

In the illustrated embodiment of FIGS. 3-9, and as best seen in FIG. 3,the shank 40 has an outer surface 52 in contact with the trabecularmeshwork 21 surrounding the cavity 50. For stabilization purposes, theshank outer surface 52 may comprise a studded surface, a ribbed surface,a surface with pillars, a textured surface, or the like.

In the illustrated embodiment of FIGS. 3-9, the snorkel lumen 42 has aninlet port, opening or orifice 54 at the seat top surface 44 and anoutlet port, opening or orifice 56 at the junction of the shank 40 andblade 34. The lumen 42 is generally cylindrical in shape, that is, ithas a generally circular cross-section, and its ports 54, 56 aregenerally circular in shape. In modified embodiments, the lumen 42 andports 54, 56 may be efficaciously shaped in other manners, as requiredor desired, giving due consideration to the goals of providingsufficient aqueous outflow and/or of achieving one or more of thebenefits and advantages as taught or suggested herein. For example, thelumen 42 and/or one or both ports 54, 56 may be shaped in the form ofovals, ellipsoids, and the like, or the lumen 42 may have a tapered orstepped configuration.

Referring in particular to FIG. 3, aqueous from the anterior chamber 20flows into the lumen 42 through the inlet port 54 (as generallyindicated by arrow 58) and out of the outlet port 56 and into Schlemm'scanal 22 (as generally indicated by arrows 60) to lower and/or balancethe intraocular pressure (IOP). In another embodiment, as discussed infurther detail below, one or more of the outlet ports may be configuredto face in the general direction of the stent longitudinal axis 36. Inmodified embodiments, the snorkel 32 may comprise more than one lumen,as needed or desired, to facilitate multiple aqueous outflowtransportation into Schlemm's canal 22.

In the illustrated embodiment of FIGS. 3-9, the blade longitudinal axis36 and the snorkel longitudinal axis 43 are generally perpendicular toone another. Stated differently, the projections of the axes 36, 43 on acommon plane which is not perpendicular to either of the axes 36, 43intersect at 90°. The blade longitudinal axis 36 and the snorkellongitudinal axis 43 may intersect one another or may be offset from oneanother.

In the illustrated embodiment of FIGS. 3-9, the main body portion orblade 34 is a generally curved elongated sheet- or plate-like structurewith an upper curved surface 62 and a lower curved surface 64, whichdefines a trough or open face channel 66. The perimeter of the blade 34is generally defined by a curved proximal edge 68 proximate to thesnorkel 32, a curved distal edge 70 spaced from the proximal edge 68 bya pair of generally straight lateral edges 72, 74. The first lateraledge 72 extends beyond the second lateral edge 74 and intersects withthe distal edge 70 at a distal-most point 76 of the blade 34.Preferably, the blade 34 defines a blade cutting tip 78.

In the illustrated embodiment of FIGS. 3-9, and as shown in the enlargedview of FIG. 9, the cutting tip 78 comprises a first cutting edge 80 onthe distal edge 70 and a second cutting edge 82 on the lateral edge 72.The cutting edges 80, 82 preferably extend from the distal-most point 76of the blade 34 and comprise at least a respective portion of the distaledge 70 and lateral edge 72. The respective cutting edges 80, 82 areformed at the sharp edges of respective beveled or tapered surfaces 84,86. In one embodiment, the remainder of the distal edge 70 and lateraledge 72 are dull or rounded. In one embodiment, the tip 78 proximate tothe distal-most end 76 is curved slightly inwards, as indicatedgenerally by the arrow 88 in FIG. 5 and arrow 88 (pointed perpendicularand into the plane of the paper) in FIG. 9, relative to the adjacentcurvature of the blade 34.

In modified embodiments, suitable cutting edges may be provided onselected portions of one or more selected blade edges 68, 70, 72, 74with efficacy, as needed or desired, giving due consideration to thegoals of providing suitable cutting means on the stent 30 foreffectively cutting through the trabecular meshwork 21 (FIG. 3) and/orof achieving one or more of the benefits and advantages as taught orsuggested herein.

Referring in particular to FIG. 9, in one embodiment, the ratio betweenthe lengths of the cutting edges 80, 82 is about 2:1. In anotherembodiment, the ratio between the lengths of the cutting edges 80, 82 isabout 1:1. In yet another embodiment, the ratio between the lengths ofthe cutting edges 80, 82 is about 1:2. In modified embodiments, thelengths of the cutting edges 80, 82 may be efficaciously selected inother manners, as required or desired, giving due consideration to thegoals of providing suitable cutting means on the stent 30 foreffectively cutting through the trabecular meshwork 21 (FIG. 3) and/orof achieving one or more of the benefits and advantages as taught orsuggested herein.

Still referring in particular to FIG. 9, in one embodiment, the ratiobetween the lengths of the cutting edges 80, 82 is in the range fromabout 2:1 to about 1:2. In another embodiment, the ratio between thelengths of the cutting edges 80, 82 is in the range from about 5:1 toabout 1:5. In yet another embodiment, the ratio between the lengths ofthe cutting edges 80, 82 is in the range from about 10:1 to about 1:10.In modified embodiments, the lengths of the cutting edges 80, 82 may beefficaciously selected in other manners, as required or desired, givingdue consideration to the goals of providing suitable cutting means onthe stent 30 for effectively cutting through the trabecular meshwork 21(FIG. 3) and/or of achieving one or more of the benefits and advantagesas taught or suggested herein.

As shown in the top view of FIG. 9, the cutting edge 80 (and/or thedistal end 70) and the cutting edge 82 (and/or the lateral edge 72)intersect at an angle θ. Stated differently, θ is the angle between theprojections of the cutting edge 80 (and/or the distal end 70) and thecutting edge 82 (and/or the lateral edge 72) on a common plane that isnot perpendicular to either of these edges.

Referring to in particular to FIG. 9, in one embodiment, the angle θ isabout 50°. In another embodiment, the angle θ is in the range from about40° to about 60°. In yet another embodiment, the angle θ is in the rangefrom about 30° to about 70°. In modified embodiments, the angle θ may beefficaciously selected in other manners, as required or desired, givingdue consideration to the goals of providing suitable cutting means onthe stent 30 for effectively cutting through the trabecular meshwork 21(FIG. 3) and/or of achieving one or more of the benefits and advantagesas taught or suggested herein.

The stent 30 of the embodiments disclosed herein can be dimensioned in awide variety of manners. Referring in particular to FIG. 3, the depth ofSchlemm's canal 22 is typically about less than 400 microns (μm).Accordingly, the stunt blade 34 is dimensioned so that the height of theblade 34 (referred to as H₄₁ in FIG. 4) is typically less than about 400μm. The snorkel shank 40 is dimensioned so that it has a length(referred to as L₄₁ in FIG. 4) typically in the range from about 150 μmto about 400 μm, which is roughly the typical range of the thickness ofthe trabecular meshwork 21.

Of course, as the skilled artisan will appreciate, that with the stent30 implanted, the blade 34 may rest at any suitable position withinSchlemm's canal 22. For example, the blade 34 may be adjacent to a frontwall 90 of Schlemm's canal 22 (as shown in FIG. 3), or adjacent to aback wall 92 of Schlemm's canal 22, or at some intermediate locationtherebetween, as needed or desired. Also, the snorkel shank 40 mayextend into Schlemm's canal 22. The length of the snorkel shank 40and/or the dimensions of the blade 34 may be efficaciously adjusted toachieve the desired implant positioning.

The trabecular stenting device 30 (FIGS. 3-9) of the exemplaryembodiment may be manufactured or fabricated by a wide variety oftechniques. These include, without limitation, molding, thermo-forming,or other micro-machining techniques, among other suitable techniques.

The trabecular stenting device 30 preferably comprises a biocompatiblematerial such that inflammation arising due to irritation between theouter surface of the device 30 and the surrounding tissue is minimized.Biocompatible materials which may be used for the device 30 preferablyinclude, but are not limited to, titanium, titanium alloys, medicalgrade silicone, e.g., Silastic™, available from Dow Coming Corporationof Midland, Mich.; and polyurethane, e.g., Pellethane™, also availablefrom Dow Corning Corporation.

In other embodiments, the stent device 30 may comprise other types ofbiocompatible material, such as, by way of example, polyvinyl alcohol,polyvinyl pyrrolidone, collagen, heparinized collagen,polytetrafluoroethylene, expanded polytetrafluoroethylene, fluorinatedpolymer, fluorinated elastomer, flexible fused silica, polyolefin,polyester, polysilicon, and/or a mixture of the aforementionedbiocompatible materials, and the like. In still other embodiments,composite biocompatible material may be used, wherein a surface materialmay be used in addition to one or more of the aforementioned materials.For example, such a surface material may include polytetrafluoroethylene(PTFE) (such as Teflon™), polyimide, hydrogel, heparin, therapeuticdrugs (such as beta-adrenergic antagonists and other anti-glaucomadrugs, or antibiotics), and the like.

In an exemplary embodiment of the trabecular meshwork surgery, thepatient is placed in the supine position, prepped, draped andanesthetized as necessary. A small (less than about 1 mm) incision,which may be self sealing, can then be made through the cornea 12. Thecorneal incision can be made in a number of ways, for example, by usinga micro-knife, among other tools.

An applicator or delivery apparatus is used to advance the glaucomastent 30 through the corneal incision and to the trabecular meshwork 21.Some embodiments of such a delivery apparatus are disclosed in copendingU.S. application Ser. No. 10/101,548, filed Mar. 18, 2002, entitledAPPLICATOR AND METHODS FOR PLACING A TRABECULAR SHUNT FOR GLAUCOMATREATMENT, and U.S. Provisional Application No. 60/276,609, filed Mar.16, 2001, entitled APPLICATOR AND METHODS FOR PLACING A TRABECULAR SHUNTFOR GLAUCOMA TREATMENT, the entire contents of each one of which arehereby incorporated by reference herein. Some embodiments of a deliveryapparatus are also described in further detail below. Gonioscopic,microscopic, or endoscopic guidance can be used during the trabecularmeshwork surgery.

With the device 30 held by the delivery apparatus, the blade 34 of thedevice 30 is used to cut and/or displace the material of the trabecularmeshwork 21. The snorkel shank 40 can also facilitate in removal of thismaterial during implantation. The delivery apparatus is withdrawn oncethe device 30 has been implanted in the eye 10. As shown in FIG. 3, thesnorkel seat 38 can rest on a top surface 94 of the trabecular meshwork21 with the snorkel shank 40 extending through the cavity 50 (created bythe device 30) in the trabecular meshwork 21, and with the blade 34extending inside Schlemm's canal 22.

Advantageously, the embodiments of the self-trephining stent device 30allow for a “one-step” procedure to make an incision in the trabecularmeshwork and to implant the stent in the proper orientation andalignment within the eye to allow outflow of aqueous from the anteriorchamber through the stent and into Schlemm's canal to lower and/orbalance the intraocular pressure (TOP). Desirably, this provides for afaster, safer, and less expensive surgical procedure.

Many complications can arise in trabecular meshwork surgeries, wherein aknife is first used to create an incision in the trabecular meshwork,followed by removal of the knife and subsequent installation of thestent. For instance, the knife may cause some bleeding which clouds upthe surgical site. This may require more effort and time to clean thesurgical site prior to placement of the stent. Moreover, this may causethe intraocular pressure (IOP) to rise or to fall undesirably. Thus,undesirably, such a multiple step procedure may demand crisis managementthat slows down the surgery, makes it less safe, and more expensive.

FIG. 14 is a simplified partial view of an eye 10 illustrating theimplantation of a self-trephining glaucoma stent device 30 a havingfeatures and advantages in accordance with one embodiment. The stent 30a is generally similar to the stent 30 of FIGS. 3-9 except that itssnorkel 32 a comprises a longer shank 40 a, which extends into Schlemm'scanal 22 and a lumen 42 a, which bifurcates into two output channels 45a.

In the illustrated embodiment of FIG. 14, the shank 40 a terminates atthe blade 34. Aqueous flows from the anterior chamber 20 into the lumen42 a through an inlet port 54 a (as generally indicated by arrow 58 a).Aqueous then flows through the output channels 45 a and out ofrespective outlet ports 56 a and into Schlemm's canal 22 (as generallyindicated by arrows 60 a). The outlet channels 45 a extend radiallyoutwards in generally opposed directions and the outlet ports 56 a areconfigured to face in the general direction of the stent longitudinalaxis 36 so that they open into Schlemm's canal 22 and are in properorientation to allow aqueous outflow into Schlemm's canal 22 forlowering and/or balancing the intraocular pressure (IOP). As indicatedabove, fiducial marks or indicia and/or predetermined shapes of thesnorkel seat 38 allow for proper orientation of the blade 34 and alsothe output channels 45 a and respective ports 56 a within Schlemm'scanal.

In the illustrated embodiment of FIG. 14, two outflow channels 45 a areprovided. In another embodiment, only one outflow channel 45 a isprovided. In yet another embodiment, more than two outflow channels 45 aare provided. In modified embodiments, the lumen 42 a may extend all theway through to the blade 34 and provide an outlet port as discussedabove with reference to the embodiment of FIGS. 3-9.

FIG. 15 is a simplified partial view of an eye 10 illustrating theimplantation of a self-trephining glaucoma stent device 30 b havingfeatures and advantages in accordance with one embodiment. The stent 30b is generally similar to the stent 30 of FIGS. 3-9 except that itssnorkel 32 b comprises a longer shank 40 b, which extends into Schlemm'scanal 22 and a lumen 42 b, which bifurcates into two output channels 45b.

In the illustrated embodiment of FIG. 15, the shank 40 b extends throughthe blade 34. Aqueous flows from the anterior chamber 20 into the lumen42 b through an inlet port 54 b (as generally indicated by arrow 58 b).Aqueous then flows through the output channels 45 b and out ofrespective outlet ports 56 b and into Schlemm's canal 22 (as generallyindicated by arrows 60 b). The outlet channels 45 b extend radiallyoutwards in generally opposed directions and the outlet ports 56 b areconfigured to face in the general direction of the stent longitudinalaxis 36 so that they open into Schlemm's canal 22 and are in properorientation to allow aqueous outflow into Schlemm's canal 22 forlowering and/or balancing the intraocular pressure (IOP). As indicatedabove, fiducial marks or indicia and/or predetermined shapes of thesnorkel seat 38 allow for proper orientation of the blade 34 and alsothe output channels 45 b and respective ports 56 b within Schlemm'scanal.

In the illustrated embodiment of FIG. 15, two outflow channels 45 b areprovided. In another embodiment, only one outflow channel 45 b isprovided. In yet another embodiment, more than two outflow channels 45 bare provided. In modified embodiments, the lumen 42 b may extend all theway through to the blade 34 and provide an outlet port as discussedabove with reference to the embodiment of FIGS. 3-9.

FIGS. 16-20 show different views of a self-trephining glaucoma stentdevice 30 c having features and advantages in accordance with oneembodiment. The stent 30 c is generally similar to the stent 30 of FIGS.3-9 except that it has a modified blade configuration. The stent 30 ccomprises a blade 34 c which is a generally curved elongated sheet- orplate-like structure with an upper curved surface 62 c and a lowercurved surface 64 c which defines a trough or open face channel 66 c.The perimeter of the blade 34 c is generally defined by a curvedproximal edge 68 c proximate to the snorkel 32, a curved distal edge 70c spaced from the proximal edge 68 c by a pair of generally straightlateral edges 72 c, 74 c which are generally parallel to one another andhave about the same length.

In the illustrated embodiment of FIGS. 16-20, the blade 34 c comprises acutting tip 78 c. The cutting tip 78 c preferably includes cutting edgesformed on selected portions of the distal edge 70 c and adjacentportions of the lateral edges 72 c, 74 c for cutting through thetrabecular meshwork for placement of the snorkel 32. The cutting edgesare sharp edges of beveled or tapered surfaces as discussed above inreference to FIG. 9. The embodiment of FIGS. 16-20 may be efficaciouslymodified to incorporate the snorkel configuration of the embodiments ofFIGS. 14 and 15.

FIGS. 21-25 show different views of a self-trephining glaucoma stentdevice 30 d having features and advantages in accordance with oneembodiment. The stent 30 d is generally similar to the stent 30 of FIGS.3-9 except that it has a modified blade configuration. The stent 30 dcomprises a blade 34 d which is a generally curved elongated sheet- orplate-like structure with an upper curved surface 62 d and a lowercurved surface 64 d which defines a trough or open face channel 66 d.The perimeter of the blade 34 d is generally defined by a curvedproximal edge 68 d proximate to the snorkel 32, a pair of inwardlyconverging curved distal edges 70 d′, 70 d″ spaced from the proximaledge 68 d by a pair of generally straight respective lateral edges 72 d,74 d which are generally parallel to one another and have about the samelength. The distal edges 70 d′, 70 d″ intersect at a distal-most point76 d of the blade 34 d proximate a blade cutting tip 78 d.

In the illustrated embodiment of FIGS. 21-25, the cutting tip 78 dpreferably includes cutting edges formed on the distal edges 70 d′, 70d″ and extending from the distal-most point 76 d of the blade 34 d. Inone embodiment, the cutting edges extend along only a portion ofrespective distal edges 70 d′, 70 d″ In another embodiment, the cuttingedges extend along substantially the entire length of respective distaledges 70 d′, 70 d″ In yet another embodiment, at least portions of thelateral edges 72 d, 74 d proximate to respective distal edges 70 d′, 70d″ have cutting edges. In a further embodiment, the tip 78 d proximateto the distal-most end 76 d is curved slightly inwards, as indicatedgenerally by the arrow 88 d in FIG. 21 and arrow 88 d (pointedperpendicular and into the plane of the paper) in FIG. 22, relative tothe adjacent curvature of the blade 34 d.

In the embodiment of FIGS. 21-25, the cutting edges are sharp edges ofbeveled or tapered surfaces as discussed above in reference to FIG. 9.The embodiment of FIGS. 21-25 may be efficaciously modified toincorporate the snorkel configuration of the embodiments of FIGS. 14 and15.

FIGS. 26-28 show different views of a self-trephining glaucoma stentdevice 30 e having features and advantages in accordance with oneembodiment. The stent device 30 e generally comprises a snorkel 32 emechanically connected to or in mechanical communication with a blade orcutting tip 34 e. The snorkel 32 e has a seat, head or cap portion 38 emechanically connected to or in mechanical communication with a shank 40e, as discussed above. The shank 40 e has a distal end or base 47 e. Thesnorkel 32 e further has a lumen 42 e, which bifurcates into a pair ofoutlet channels 45 e, as discussed above in connection with FIGS. 14 and15. Other lumen and inlet and outlet port configurations as taught orsuggested herein may also be efficaciously used, as needed or desired.

In the illustrated embodiment of FIGS. 26-28, the blade 34 e extendsdownwardly and outwardly from the shank distal end 47 e. The blade 34 eis angled relative to a generally longitudinal axis 43 e of the snorkel32 e, as best seen in FIGS. 27 and 28. The blade 34 e has a distal-mostpoint 76 e. The blade or cutting tip 34 e has a pair of side edges 70e′, 70 e,″ including cutting edges, terminating at the distal-most point76 e, as best seen in FIG. 26. In one embodiment, the cutting edges aresharp edges of beveled or tapered surfaces as discussed above inreference to FIG. 9.

Referring to FIGS. 26-28, in one embodiment, the blade 34 e includescutting edges formed on the edges 70 e′, 70 e″ and extending from thedistal-most point 76 e of the blade 34 d. In one embodiment, the cuttingedges extend along only a portion of respective distal edges 70 e′, 70e″ In another embodiment, the cutting edges extend along substantiallythe entire length of respective distal edges 70 e′, 70 e″ In yet anotherembodiment, the blade or cutting tip 34 e comprises a bent tip ofneedle, for example, a 30 gauge needle.

In general, any of the blade configurations disclosed herein may be usedin conjunction with any of the snorkel configurations disclosed hereinor incorporated by reference herein to provide a self-trephiningglaucoma stent device for making an incision in the trabecular meshworkfor receiving the corresponding snorkel to provide a pathway for aqueousoutflow from the eye anterior chamber to Schlemm's canal, therebyeffectively lowering and/or balancing the intraocular pressure (IOP).The self-trephining ability of the device, advantageously, allows for a“one-step” procedure in which the incision and placement of the snorkelare accomplished by a single device and operation. In any of theembodiments, fiducial markings or indicia, and/or preselectedconfiguration of the snorkel seat, and/or positioning of the stentdevice in a preloaded applicator may be used for proper orientation andalignment of the device during implantation.

In many cases, a surgeon works from a temporal incision when performingcataract or goniometry surgery. FIG. 29 illustrates a temporal implantprocedure, wherein a delivery apparatus or “applicator” 100 having acurved tip 102 is used to deliver a stent 30 to a temporal side 27 ofthe eye 10. An incision 28 is made in the cornea 10, as discussed above.The apparatus 100 is then used to introduce the stent 30 through theincision 28 and implant it within the eye 10.

Still referring in particular to FIG. 29, in one embodiment, a similarlycurved instrument would be used to make the incision through thetrabecular meshwork 21. In other embodiments, a self-trephining stentdevice 30 may be used to make this incision through the trabecularmeshwork 21, as discussed above. The temporal implantation procedureillustrated in FIG. 29 may be employed with the any of the various stentembodiments taught or suggested herein.

FIG. 30 illustrates one embodiment of an apparatus comprising anarticulating stent applicator or retrieval device 100 a. In thisembodiment, a proximal arm 106 is attached to a distal arm 108 at ajoint 112. This joint 112 is movable such that an angle formed betweenthe proximal arm 106 and the distal arm 108 can change. One or moreclaws 114 can extend from the distal arm 108, in the case of a stentretrieval device. Similarly, this articulation mechanism may be used forthe trabecular stent applicator, and thus the articulating applicator orretrieval device 100 a may be either an applicator for the trabecularstent, a retrieval device, or both, in various embodiments. Theembodiment of FIG. 30 may be employed with the any of the various stentembodiments taught or suggested herein.

FIG. 31 shows another illustrative method for placing any of the variousstent embodiments taught or suggested herein at the implant site withinthe eye 10. A delivery apparatus 100 b generally comprises a syringeportion 116 and a cannula portion 118. The distal section of the cannula118 has at least one irrigating hole 120 and a distal space 122 forholding the stent device 30. The proximal end 124 of the lumen of thedistal space 122 is sealed from the remaining lumen of the cannulaportion 118. The delivery apparatus of FIG. 30 may be employed with theany of the various stent embodiments taught or suggested herein.

In one aspect of the invention, a delivery apparatus (or “applicator”)is used for placing a trabecular stent through a trabecular meshwork ofan eye. Certain embodiments of such a delivery apparatus are disclosedin copending U.S. application Ser. No. 10/101,548, filed Mar. 18, 2002,entitled APPLICATOR AND METHODS FOR PLACING A TRABECULAR SHUNT FORGLAUCOMA TREATMENT, and U.S. Provisional Application No. 60/276,609,filed Mar. 16, 2001, entitled APPLICATOR AND METHODS FOR PLACING ATRABECULAR SHUNT FOR GLAUCOMA TREATMENT, the entire contents of each oneof which are hereby incorporated by reference herein.

The stent has an inlet section and an outlet section. The deliveryapparatus includes a handpiece, an elongate tip, a holder and anactuator. The handpiece has a distal end and a proximal end. Theelongate tip is connected to the distal end of the handpiece. Theelongate tip has a distal portion and is configured to be placed througha corneal incision and into an anterior chamber of the eye. The holderis attached to the distal portion of the elongate tip. The holder isconfigured to hold and release the inlet section of the trabecularstent. The actuator is on the handpiece and actuates the holder torelease the inlet section of the trabecular stent from the holder. Whenthe trabecular stent is deployed from the delivery apparatus into theeye, the outlet section is positioned in substantially oppositedirections inside Schlemm's canal. In one embodiment, a deploymentmechanism within the delivery apparatus includes a push-pull typeplunger.

In some embodiments, the holder comprises a clamp. In some embodiments,the apparatus further comprises a spring within the handpiece that isconfigured to be loaded when the stent is being held by the holder, thespring being at least partially unloaded upon actuating the actuator,allowing for release of the stent from the holder.

In various embodiments, the clamp comprises a plurality of clawsconfigured to exert a clamping force onto the inlet section of thestent. The holder may also comprise a plurality of flanges.

In some embodiments, the distal portion of the elongate tip is made of aflexible material. This can be a flexible wire. The distal portion canhave a deflection range, preferably of about 45 degrees from the longaxis of the handpiece.

The delivery apparatus can further comprise an irrigation port in theelongate tip.

Some aspects include a method of placing a trabecular stent through atrabecular meshwork of an eye, the stent having an inlet section and anoutlet section, including advancing a delivery apparatus holding thetrabecular stent through an anterior chamber of the eye and into thetrabecular meshwork, placing part of the stent through the trabecularmeshwork and into a Schlemm's canal of the eye; and releasing the stentfrom the delivery apparatus.

In various embodiments, the method includes using a delivery apparatusthat comprises a handpiece having a distal end and a proximal end; anelongate tip connected to the distal end of the handpiece, the elongatetip having a distal portion and being configured to be placed through acorneal incision and into an anterior chamber of the eye; a holderattached to the distal portion of the elongate tip, the holderconfigured to hold and release the inlet section of the trabecularstent; and an actuator on the handpiece that actuates the holder torelease the inlet section of the trabecular stent from the holder.

In one aspect, the trabecular stent is removably attached to a deliveryapparatus (also known as “applicator”). When the trabecular stent isdeployed from the delivery apparatus into the eye, the outlet section ispositioned in substantially opposite directions inside Schlemm's canal.In one embodiment, a deployment mechanism within the delivery apparatusincludes a push-pull type plunger. In some embodiments, the deliveryapplicator may be a guidewire, an expandable basket, an inflatableballoon, or the like.

Screw/Barb Anchored Stent

FIGS. 32 and 33 illustrate a glaucoma stent device 30 f having featuresand advantages in accordance with one embodiment. This embodiment of thetrabecular stent 30 f includes a barbed or threaded screw-like extensionor pin 126 with barbs 128 for anchoring. The barbed pin 126 extends froma distal or base portion 130 of the stent 30 f.

In use, the stent 30 f (FIG. 32) is advanced through the trabecularmeshwork 21 and across Schlemm's canal 22. The barbed (or threaded)extension 126 penetrates into the back wall 92 of Schlemm's canal 22 upto the shoulder or base 130 that then rests on the back wall 92 of thecanal 22. The combination of a shoulder 130 and a barbed pin 126 of aparticular length limits the penetration depth of the barbed pin 126 toa predetermined or preselected distance. In one embodiment, the lengthof the pin 126 is about 0.5 mm or less. Advantageously, this barbedconfiguration provides a secure anchoring of the stent 30 f. Asdiscussed above, correct orientation of the stent 30 f is ensured byappropriate fiducial marks, indicia or the like and by positioning ofthe stent in a preloaded applicator.

Referring to FIG. 32, the aqueous flows from the anterior chamber 20,through the lumen 42 f, then out through two side-ports 56 f to bedirected in both directions along Schlemm's canal 22. Alternatively,flow could be directed in only one direction through a single side-port56 f. In other embodiments, more then two outlet ports 56 f, forexample, six to eight ports (like a pin wheel configuration), may beefficaciously used, as needed or desired.

Still referring to FIG. 32, in one embodiment, the stent 30 f isinserted through a previously made incision in the trabecular meshwork21. In other embodiments, the stent 30 f may be combined with any of theblade configurations taught or suggested herein to provideself-trephining capability. In these cases, the incision through thetrabecular meshwork 21 is made by the self-trephining stent device thathas a blade at its base or proximate to the base.

Deeply Threaded Stent

FIG. 34 illustrates a glaucoma stent device 30 g having features andadvantages in accordance with one embodiment. The stent 30 g has a heador seat 38 g and a shank or main body portion 40 g with a base or distalend 132. This embodiment of the trabecular stent 30 g includes a deepthread 134 (with threads 136) on the main body 40 g of the stent 30 gbelow the head 38 g. The threads may or may not extend all the way tothe base 132.

In use, the stent 30 g (FIG. 34) is advanced through the meshwork 21through a rotating motion, as with a conventional screw. Advantageously,the deep threads 136 provide retention and stabilization of the stent 30g in the trabecular meshwork 21.

Referring to FIG. 34, the aqueous flows from the anterior chamber 20,through the lumen 42 g, then out through two side-ports 56 g to bedirected in both directions along Schlemm's canal 22. Alternatively,flow could be directed in only one direction through a single side-port56 g. In other embodiments, more then two outlet ports 56 g may beefficaciously used, as needed or desired.

One suitable applicator or delivery apparatus for this stent 30 g (FIG.34) includes a preset rotation, for example, via a wound torsion springor the like. The rotation is initiated by a release trigger on theapplicator. A final twist of the applicator by the surgeon andobservation of suitable fiducial marks, indicia or the like ensureproper alignment of the side ports 56 g with Schlemm's canal 22.

Referring to FIG. 34, in one embodiment, the stent 30 g is insertedthrough a previously made incision in the trabecular meshwork 21. Inother embodiments, the stent 30 g may be combined with any of the bladeconfigurations taught or suggested herein to provide self-trephiningcapability. In these cases, the incision through the trabecular meshwork21 is made by the self-trephining stent device that has a blade at itsbase or proximate to the base.

Rivet Style Stent

FIG. 35 illustrates a glaucoma stent device 30 h having features andadvantages in accordance with one embodiment. The stent has a base ordistal end 138. This embodiment of the trabecular stent 30 h has a pairof flexible ribs 140. In the unused state, the ribs are initiallygenerally straight (that is, extend in the general direction of arrow142).

Referring to FIG. 35, upon insertion of the stent 30 h through thetrabecular meshwork 21, the ends 144 of respective ribs 140 of the stent30 h come to rest on the back wall 92 of Schlemm's canal 22. Furtheradvancement of the stent 30 h causes the ribs 140 to deform to the bentshape as shown in the drawing of FIG. 35. The ribs 140 are designed tofirst buckle near the base 138 of the stent 30 h. Then the bucklingpoint moves up the ribs 140 as the shank part 40 h of the stent 30 h isfurther advanced through the trabecular meshwork 21.

The lumen 42 h (FIG. 35) in the stent 30 h is a simple straight hole.The aqueous flows from the anterior chamber 20, through the lumen 42 h,then out around the ribs 140 to the collector channels further alongSchlemm's canal 22 in either direction.

Referring to FIG. 35, in one embodiment, the stent 30 h is insertedthrough a previously made incision in the trabecular meshwork 21. Inother embodiments, the stent 30 h may be combined with any of the bladeconfigurations taught or suggested herein to provide self-trephiningcapability. In these cases, the incision through the trabecular meshwork21 is made by the self-trephining stent device that has a blade at itsbase or proximate to the base.

Grommet Style Stent

FIG. 36 illustrates a glaucoma stent device 30 i having features andadvantages in accordance with one embodiment. This embodiment of thetrabecular stent 30 i includes a head or seat 38 i, a tapered baseportion 146 and an intermediate narrower waist portion or shank 40 i.

In use, the stent 30 i (FIG. 36) is advanced through the trabecularmeshwork 21 and the base 146 is pushed into Schlemm's canal 22. Thestent 30 i is pushed slightly further, if necessary, until the meshwork21 stretched by the tapered base 146 relaxes back and then contracts toengage the smaller diameter portion waist 40 i of the stent 30 i.Advantageously, the combination of the larger diameter head or seat 38 iand base 146 of the stent 30 i constrains undesirable stent movement. Asdiscussed above, correct orientation of the stent 30 i is ensured byappropriate fiducial marks, indicia or the like and by positioning ofthe stent in a preloaded applicator.

Referring to FIG. 36, the aqueous flows from the anterior chamber 20,through the lumen 42 i, then out through two side-ports 56 i to bedirected in both directions along Schlemm's canal 22. Alternatively,flow could be directed in only one direction through a single side-port56 i. In other embodiments, more then two outlet ports 56 i may beefficaciously used, as needed or desired.

Still referring to FIG. 36, in one embodiment, the stent 30 i isinserted through a previously made incision in the trabecular meshwork21. In other embodiments, the stent 30 i may be combined with any of theblade configurations taught or suggested herein to provideself-trephining capability. In these cases, the incision through thetrabecular meshwork 21 is made by the self-trephining stent device,which has a blade at its base or proximate to the base.

Biointeractive Stent

FIG. 37 illustrates a glaucoma stent device 30 j having features andadvantages in accordance with one embodiment. This embodiment of thetrabecular stent 30 j utilizes a region of biointeractive material 148that provides a site for the trabecular meshwork 21 to firmly grip thestent 30 j by ingrowth of the tissue into the biointeractive material148. As shown in FIG. 37, preferably the biointeractive layer 148 isapplied to those surfaces of the stent 30 j, which would abut against orcome in contact with the trabecular meshwork 21.

In one embodiment, the biointeractive layer 148 (FIG. 37) may be aregion of enhanced porosity with a growth promoting chemical. In oneembodiment, a type of bio-glue 150 that dissolves over time is used tohold the stent secure during the time between insertion and sufficientingrowth for stabilization. As discussed above, correct orientation ofthe stent 30 j is ensured by appropriate fiducial marks, indicia or thelike and by positioning of the stent in a preloaded applicator.

Referring to FIG. 37, the aqueous flows from the anterior chamber 20,through the lumen 42 j, then out through two side-ports 56 j to bedirected in both directions along Schlemm's canal 22. Alternatively,flow could be directed in only one direction through a single side-port56 j. In other embodiments, more then two outlet ports 56 j may beefficaciously used, as needed or desired.

Still referring to FIG. 37, in one embodiment, the stent 30 j isinserted through a previously made incision in the trabecular meshwork21. In other embodiments, the stent 30 j may be combined with any of theblade configurations taught or suggested herein to provideself-trephining capability. In these cases, the incision through thetrabecular meshwork 21 is made by the self-trephining stent device,which has a blade at its base or proximate to the base.

Glued or Welded Stent

FIG. 38 illustrates a glaucoma stent device 30 k having features andadvantages in accordance with one embodiment. This embodiment of thetrabecular stent 30 k is secured in place by using a permanent(non-dissolving) bio-glue 152 or a “welding” process (e.g., heat) toform a weld 152. The stent 30 k has a head or seat 38 k and a lowersurface 46 k.

The stent 30 k is advanced through the trabecular meshwork 21 until thehead or seat 38 k comes to rest on the trabecular meshwork 21, that is,the head lower surface 46 k abuts against the trabecular meshwork 21,and the glue or weld 152 is applied or formed therebetween, as shown inFIG. 38. As discussed above, correct orientation of the stent 30 k isensured by appropriate fiducial marks, indicia or the like and bypositioning of the stent in a preloaded applicator.

Referring to FIG. 38, the aqueous flows from the anterior chamber 20,through the lumen 42 k, then out through two side-ports 56 k to bedirected in both directions along Schlemm's canal 22. Alternatively,flow could be directed in only one direction through a single side-port56 k. In other embodiments, more then two outlet ports 56 k may beefficaciously used, as needed or desired.

Still referring to FIG. 38, in one embodiment, the stent 30 k isinserted through a previously made incision in the trabecular meshwork21. In other embodiments, the stent 30 k may be combined with any of theblade configurations taught or suggested herein to provideself-trephining capability. In these cases, the incision through thetrabecular meshwork 21 is made by the self-trephining stent device,which has a blade at its base or proximate to the base.

Hydrophilic Latching Stent

FIG. 39 illustrates a glaucoma stent device 30 m having features andadvantages in accordance with one embodiment. This embodiment of thetrabecular stent 30 m is fabricated from a hydrophilic material thatexpands with absorption of water. Desirably, this would enable thedevice 30 m to be inserted through a smaller incision in the trabecularmeshwork 21. The subsequent expansion (illustrated by the smaller arrows154) of the stent 30 m would advantageously enable it to latch in placein the trabecular meshwork 21. As discussed above, correct orientationof the stent 30 m is ensured by appropriate fiducial marks, indicia orthe like and by positioning of the stent in a preloaded applicator.

Referring to FIG. 39, the aqueous flows from the anterior chamber 20,through the lumen 42 m, then out through two side-ports 56 m to bedirected in both directions along Schlemm's canal 22. Alternatively,flow could be directed in only one direction through a single side-port56 m. In other embodiments, more then two outlet ports 56 m may beefficaciously used, as needed or desired.

Still referring to FIG. 39, in one embodiment, the stent 30 m isinserted through a previously made incision in the trabecular meshwork21. In other embodiments, the stent 30 m may be combined with any of theblade configurations taught or suggested herein to provideself-trephining capability. In these cases, the incision through thetrabecular meshwork 21 is made by the self-trephining stent device,which has a blade at its base or proximate to the base.

Photodynamic Stent

FIG. 40 illustrates a glaucoma stent device 30 n having features andadvantages in accordance with one embodiment. This embodiment of thetrabecular stent 30 n is fabricated from a photodynamic material thatexpands on exposure to light.

It is commonly known that there is a diurnal variation in the aqueoushumor production by the eye—it is higher during the day than it is atnight. The lumen 42 n of the stent 30 n responds to light entering thecornea during the day by expanding and allowing higher flow of aqueousthrough the lumen 42 n and into Schlemm's canal 22. This expansion isgenerally indicated by the smaller arrows 156 (FIG. 40) which show thelumen 42 n (and ports) expanding or opening in response to lightstimulus. (The light or radiation energy E is generally given by E=hv,where h is Planck's constant and v is the frequency of the lightprovided.) At night, in darkness, the lumen diameter decreases andreduces the flow allowed through the lumen 42 n. In one embodiment, anexcitation wavelength that is different from that commonly encounteredis provided on an as-needed basis to provide higher flow of aqueous toSchlemm's canal 22.

This photodynamic implementation is shown in FIG. 40 for theself-latching style of stent 30 n, but can be efficaciously used withany of the other stent embodiments, as needed or desired. As discussedabove, correct orientation of the stent 30 n is ensured by appropriatefiducial marks, indicia or the like and by positioning of the stent in apreloaded applicator.

Referring to FIG. 40, the aqueous flows from the anterior chamber 20,through the lumen 42 n, then out through two side-ports 56 n to bedirected in both directions along Schlemm's canal 22. Alternatively,flow could be directed in only one direction through a single side-port56 n. In other embodiments, more then two outlet ports 56 n may beefficaciously used, as needed or desired.

Still referring to FIG. 40, in one embodiment, the stent 30 n isinserted through a previously made incision in the trabecular meshwork21. In other embodiments, the stent 30 n may be combined with any of theblade configurations taught or suggested herein to provideself-trephining capability. In these cases, the incision through thetrabecular meshwork 21 is made by the self-trephining stent device,which has a blade at its base or proximate to the base.

Collector Channel Alignment Stent

FIG. 41 illustrates a glaucoma stent device 30 p having features andadvantages in accordance with one embodiment. This figure depicts anembodiment of a stent 30 p that directs aqueous from the anteriorchamber 20 directly into a collector channel 29, which empties intoaqueous veins. The stent 30 p has a base or distal end 160.

In the illustrated embodiment of FIG. 41, a removable alignment pin 158is utilized to align the stent lumen 42 p with the collector channel 29.In use, the pin 158 extends through the stent lumen 42 p and protrudesthrough the base 160 and extends into the collector channel 29 to centerand/or align the stent 30 p over the collector channel 29. The stent 30p is then pressed firmly against the back wall 92 of Schlemm's canal 22.A permanent bio-glue 162 is used between the stent base and the backwall 92 of Schlemm's canal 22 to seat and securely hold the stent 30 pin place. Once positioned, the pin 158 is withdrawn from the lumen 42 pto allow the aqueous to flow directly from the anterior chamber 20 intothe collector duct 29. The collector ducts are nominally 20 to 100micrometers (m) in diameter and are visualized with a suitablemicroscopy method (such as ultrasound biomicroscopy (UBM)) or laserimaging to provide guidance for placement of the stent 30 p.

Referring to FIG. 41, in one embodiment, the stent 30 p is insertedthrough a previously made incision in the trabecular meshwork 21. Inother embodiments, the stent 30 p may be combined with any of the bladeconfigurations taught or suggested herein to provide self-trephiningcapability. In these cases, the incision through the trabecular meshwork21 is made by the self-trephining stent device, which has a blade at itsbase or proximate to the base.

Barbed Stent (Anterior Chamber to Collector Channel)

FIG. 42 illustrates a glaucoma stent device 30 q having features andadvantages in accordance with one embodiment. This figure depicts anembodiment of a stent 30 q that directs aqueous from the anteriorchamber 20 directly into a collector channel 29, which empties intoaqueous veins. The stent 30 q has a base or distal end 166 and thechannel 29 has wall(s) 164.

In the illustrated embodiment of FIG. 42, a barbed, small-diameterextension or pin 168 on the stent base 166 is guided into the collectorchannel 29 and anchors on the wall(s) 164 of the channel 29. The pin 168has barbs 170 which advantageously provide anchoring of the stent 30 q.The collector ducts 29 are nominally 20 to 100 micrometers (μm) indiameter and are visualized with a suitable microscopy method (such asultrasound biomicroscopy (UBM)) or laser imaging to provide guidance forplacement of the stent.

Referring to FIG. 42, in one embodiment, the stent 30 q is insertedthrough a previously made incision in the trabecular meshwork 21. Inother embodiments, the stent 30 q may be combined with any of the bladeconfigurations taught or suggested herein to provide self-trephiningcapability. In these cases, the incision through the trabecular meshwork21 is made by the self-trephining stent device, which has a blade at itsbase or proximate to the base.

Valved Tube Stent (Anterior Chamber to Choroid)

FIG. 43 illustrates a valved tube stent device 30 r having features andadvantages in accordance with one embodiment. This is an embodiment of astent 30 r that provides a channel for flow between the anterior chamber20 and the highly vascular choroid 17. Clinically, the choroid 17 can beat pressures lower than those desired for the eye 10. Therefore, thisstent 30 r includes a valve with an opening pressure equal to thedesired pressure difference between the choroid 17 and the anteriorchamber 10 or a constriction that provide the desired pressure drop.

Osmotic Membrane (Anterior Chamber to Choroid)

FIG. 44 illustrates an osmotic membrane device 30 s having features andadvantages in accordance with one embodiment. This embodiment provides achannel for flow between the anterior chamber 20 and the highly vascularchoroid 17. The osmotic membrane 30 s is used to replace a portion ofthe endothelial layer of the choroid 17. Since the choroid 17 is highlyvascular with blood vessels, the concentration of water on the choroidside is lower than in the anterior chamber 20 of the eye 10. Therefore,the osmotic gradient drives water from the anterior chamber 20 into thechoroid 17.

Clinically, the choroid 17 (FIG. 44) can be at pressures lower thanthose desired for the eye 10. Therefore, desirably, both osmoticpressure and the physical pressure gradient are in favor of flow intothe choroid 17. Flow control is provided by proper sizing of the area ofthe membrane; the larger the membrane area is the larger the flow ratewill be. This advantageously enables tailoring to tune the flow to thedesired physiological rates.

Ab Externo Insertion of Stent Via Small Puncture

FIG. 45 illustrates the implantation of a stent 30 t using an ab externoprocedure having features and advantages in accordance with oneembodiment. In the ab externo procedure of FIG. 45, the stent 30 t isinserted into Schlemm's canal 21 with the aid of an applicator ordelivery apparatus 100 c that creates a small puncture into the eye 10from outside.

Referring to FIG. 45, the stent 30 t is housed in the applicator 100 c,and pushed out of the applicator 100 c once the applicator tip is inposition within the trabecular meshwork 21. Since the tissue surroundingthe trabecular meshwork 21 is optically opaque, an imaging technique,such as ultrasound biomicroscopy (UBM) or a laser imaging technique, isutilized. The imaging provides guidance for the insertion of theapplicator tip and the deployment of the stent 30 t. This technique canbe used with a large variety of stent embodiments with slightmodifications since the trabecular meshwork 21 is punctured from thescleral side rather than the anterior chamber side in the ab externoinsertion.

FIG. 46 a glaucoma stent device 30 u having features and advantages inaccordance with a modified embodiment. This grommet-style stent 30 u forab externo insertion is a modification of the embodiment of FIG. 36. Inthe embodiment of FIG. 46, the upper part or head 38 u is tapered whilethe lower part or base 172 is flat, as opposed to the embodiment of FIG.36. The stent 30 u is inserted from the outside of the eye 10 through apuncture in the sclera. Many of the other embodiments of stents taughtor suggested herein can be modified for similar implantation.

This ultra microscopic device 30 u (FIG. 46) can be used with (1) atargeting Lasik-type laser, or with (2) contact on eyes or with (3)combined ultrasound microscope or (4) other device inserter handpiece.

Targeted Drug Delivery to the Trabecular Meshwork

FIG. 47 illustrates a targeted drug delivery implant 30 v havingfeatures and advantages in accordance with one embodiment. This drawingis a depiction of a targeted drug delivery concept. The slow releaseimplant 30 v is implanted within the trabecular meshwork 21.

A drug that is designed to target the trabecular meshwork 21 to increaseits porosity, or improve the active transport across the endotheliallayer of Schlemm's canal 22 can be stored in this small implant 30 v(FIG. 47). Advantageously, slow release of the drug promotes the desiredphysiology at minimal dosage levels since the drug is released into thevery structure that it is designed to modify.

Dose Response

The programmed (also know as “Targeted”) stent placement refers to theintentional placement of a stent or stents at a particular location orlocations in Schlemm's canal for the purpose of providing a benefit inthe form of more optimal outflow. For example, a method can be providedwhich includes assessing the aqueous flow characteristics of an eye.Such characteristics can include, for example, but without limitation,collector channel distribution, collector channel flow characteristics,outflow resistance, outflow capacity, shape/size/tortuosity of Schlemm'scanal, and other factors). The method can also include determining anoptimal stent placement and implanting stents in one or plurality ofpositions and procedures. For example, the determination of the desiredstent placement can include consideration of a database of cadaveranatomy regarding the number and location of collector channels, thepatient's micro-anatomy data, the number of stents to be used, the typeof stents to be used, the location of any previously implanted stentswhether the desired stent is drug-loaded, gene-loaded or surfacetreated, and/or any associated drug therapy.

FIG. 48 includes a flow diagram illustrating a decision tree fordetermining desired stent placement. In the illustrated embodiment,after it is determined that a patient is suffering from excess ofintraocular pressure (TOP), a bypass flow model is determined to aid inthe decision of whether or not to use single or multiple stents.Optionally, the configuration of collector channels in the patient's eyecan be met to aid in the creation of a bypass flow model. Further, otherinformation can be used, such as, for example, but without limitation,outflow resistance, aqueous production, and venous pressure.

The bypass flow model, which can be based on the above-notedinformation, is determined so as to provide a desired strategy forlowering the excessive intraocular pressure. If it is decided that asingle stent should be used, an optimized stent location is firstdetermined based on the bypass flow model. The implantation of thesingle stent results in reduced TOP. After this implantation, it isagain determined if there is a need for further reduction in TOP. Ifadditional TOP reduction is desired, then a further bypass flow model iscreated. For example, the second bypass flow model can be determined inthe same or similar manner as the first bypass flow model describedabove. In light of the second bypass flow model, an additional stent canbe implanted at an optimized location to further reduce TOP.

If it is determined, in light of the first bypass flow model, thatmultiple stents should be used, the location of the multiple stents isfirst optimized. Then, the multiple stents are implanted. Afterwards, itis again determined if additional intraocular pressure reduction isneeded, and the trimming can continue as noted above.

Where additional stents are implanted in light of the second bypass flowmodel, the additional stents can be different from the first stentsimplanted. For example, where single or multiple stents are implanted inaccordance with the first bypass flow model, the additional stents canbe of a different type. For example, in one embodiment, the first stentis a G1 (First generation) trabecular stent that has been disclosed incopending applications and the second stent(s) is the same G1 trabecularstent. In another embodiment, the second stent(s) is different from thefirst stent; for example, the second stent is a G2 stent (that is,“injectable axisymmetric stent”; a second generation stent). In stillanother embodiment, the second stent(s) is smaller than (in some case,larger than) the first stent. The dose response may also relate to thestent configuration or characteristics such as drug-loading or surfacetreatment enabling enhancing aqueous transport or therapeutic effects onthe tissue as needed. Drug-loaded or drug-eluting stent may comprisedifferent types of drugs including, but not limited to, those cited incopending patent application Ser. No. 10/046,137 filed Nov. 8, 2001,entitled DRUG RELEASING TRABECULAR IMPLANT FOR GLAUCOMA TREATMENT, theentire contents of which is hereby incorporated by reference.

With reference to FIG. 49A, a stent extending between an anteriorchamber 20 of an eye, through the trabecular meshwork 21, and intoSchlemm's canal 22 of an eye can be configured to be axisymmetric withrespect to the flow of aqueous therethrough. For example, as shown inFIG. 49A, the stent 229A comprises an inlet end 230 configured to bedisposed in the anterior chamber 20. The second end 231 of the stent229A is configured to be disposed in Schlemm's canal 22.

At least one lumen 239 extends through the stent 229A between the inletand outlet ends 230, 232. The lumen 239 defines an opening 232 at theinlet end 230 as well as an outlet 233 at the outlet end 231.

In the illustrated embodiment, an exterior surface 238 of the stent 229Ais cone-shaped. Thus, a circumference of the exterior surface 238adjacent to the inlet end 230 is smaller than the circumference of theouter surface 238 at the outlet end 231.

With the stent 229A extending through the trabecular meshwork 21, thetissue of the trabecular meshwork 221 provides additional anchoringforce for retaining the stent 229A with its inlet end 230 in theanterior chamber and its outlet end 231 in Schlemm's canal. For example,the trabecular meshwork 21 would naturally tend to close an apertureoccupied by the stent 229A. As such, the trabecular meshwork 221 wouldtend to squeeze the stent 229A. Because the exterior surface 238 isconical, the squeezing force applied by the trabecular meshwork 221would tend to draw the stent 229A towards Schlemm's canal 22. In theillustrated embodiment, the stent 229A is sized such that a portion 234of the stent 229 adjacent to the inlet end 230 remains in the anteriorchamber 20 while a portion 235 of the stent 229 adjacent to the outletend 231 remains in Schlemm's canal 22.

In the illustrated embodiment, the outer surface 238 of the stent 229Ais straight. Alternatively, the outer surface 238 can have othercontours such as, for example, but without limitation curved or stepped.In one embodiment, the outer surface 238 can be curved in a concavemanner so as to produce a trumpet-like shape. Alternatively, the outersurface 238 can be convex.

The stent 229A preferably includes one or plurality of posts or legs 236configured to maintain a space between the outlet opening 233 and a wallof Schlemm's canal 22. As such, the legs 236 prevent a wall of Schlemm'scanal from completely closing off the outlet opening 233 of the stent229A. In the illustrated embodiment, the legs 236 are coupled to thedistal-most surface of the stent 229A and are substantially parallel toan implant axis extending through the stent 229A and between theanterior chamber 20 and Schlemm's canal 22.

This arrangement of the legs 236 and the outlet 233 imparts anaxisymmetric flow characteristic to the stent 229A. For example, aqueouscan flow from the outlet 233 in any direction. Thus, the stent 229A canbe implanted into Schlemm's canal at any angular position relative toits implant axis. Thus, it is not necessary to determine the angularorientation of the stent 229A prior to implantation, nor is it necessaryto preserve a particular orientation during an implantation procedure.

FIG. 49B illustrates a modification of the stent 229A, identifiedgenerally by the reference numeral 229B. In this embodiment, the stent229B includes a flange 237 extending radially from the portion 234.Preferably, the flange 237 is configured to retain the first portion 234within the anterior chamber 20. It is to be recognized that althoughgenerally, aqueous will flow from the anterior chamber 20 towardsSchlemm's canal 22, the stent 229A, 229B or any of the above-describedstents as well as other stents described below, can provide foromni-directional flow of aqueous.

FIG. 49C illustrates another modification of the stent 229A, identifiedgenerally by the reference numeral 229C. In this embodiment, the outersurface 238C is not conical. Rather, the outer surface 238C iscylindrical. The stent 229C includes a flange 240 that can be the samesize and shape as the flange 237. The legs 236C extend from the flange240.

Constructed as such, the natural tendency of the tissue of thetrabecular meshwork 21 to close the hole in which the stent 229C isdisposed, aids in anchoring the stent 229C in place. Additionally, thelegs 236C aid in preventing the walls of Schlemm's canal from completelyclosing the outlet 233C of the lumen 239C.

Device for Mechanically Distending Collector Duct

FIG. 50A is an enlarged cross-sectional view of a portion of the eye 10showing, anatomically, the trabecular meshwork 21, Schlemm's canal 22,and a collector duct 23 in a natural state. FIG. 50B shows a stent 229Cextending into and thereby distending the collector duct 23.

The collector duct 23 has an inner diameter identified generally by thereference numeral D₁, when in a relaxed or natural state. Because thecollector duct 23 is not typically perfectly round, the diameter D₁ cancorrespond to an “equivalent” diameter. As used herein, the equivalentdiameter can be determined by dividing the circumference of the innersurface of the collector duct 23 by π.

The stent 229D is sized to extend from the anterior chamber 20 and intothe collector duct 23. Thus, in the illustrated embodiment, the stent229D includes an upstream end portion 230D and a downstream end portion243.

The upstream portion 230D is configured to open into the anteriorchamber 20. The stent 229D is sized so as to extend from the anteriorchamber 20 and into the collector duct 23. In the illustratedembodiment, the stent 229D is sized so as to extend from the anteriorchamber 20, through the trabecular meshwork 21, through a portion ofSchlemm's canal 22, and into the collector duct 23. However, it isconceived that the stent 229D could bypass Schlemm's canal 22 and extenddirectly into a portion of the collector duct 23 downstream fromSchlemm's canal 22.

The downstream end portion 243 can have an outer diameter D₂ that islarger that the diameter D₁. Preferably, the end potion 243 is sized andconfigured for easy insertion into a collect duct 23 without injuringthe tissue or tissue surface of the collector duct 23. Thus, when theend portion 243 is disposed in the collector duct 23, the collector duct23 is distended, i.e., enlarged. As such, the resistance against theoutflow of aqueous provided by the collector duct 23 in its naturalstate can be reduced, thereby reducing TOP.

Preferably, the end portion 243 has a diameter D₂ substantially largerthan the equivalent diameter D₁ of the duct 23 so as to deform thecollector duct beyond its elastic threshold into plastic deformationregion. As such, the collector duct 23 can aid in anchoring the stent229D in place.

Applicator for Multiple Stent Implantation

FIG. 51A is a perspective view of a stent delivery applicator 201configured for multiple stent deployment. The delivery applicator 201comprises an injection sheath 246 defining a stent lumen 249, a distalstent-holding section 259, and a handle 205.

The handle 205 includes an outer surface preferably configured to begrasped by a human hand. Additionally, the handle can comprise a stentdelivery button 203. By way of example, the stent delivery button 203 isconfigured to cause a stent discharge mechanism to discharge, from theapplicator sheath 246, one stent at a time. The applicator 201 can beconfigured to store and discharge a plurality of any combination of thestents 229, 30, 30 a, 30 b, 30 c, 30 d, 30 e, 30 f, 30 g, 30 h, 30 i, 30j, 30 k, 30 m, 30 n, 30 p, 30 q, 30 r, 30 s, 30 t, 30 u, 30 v, 229A,229B, 229C, and 229D described above, the additional stents describedbelow, or any other ocular stent or implant. In the illustratedembodiment, the applicator 201 is loaded with a plurality of the stents229C

The applicator 201 can include other features as well, for example, butwithout limitation, an optional connector 209 for connecting to anexternal ultrasound power source, a fluid infusing port 204 for fluidinfusion or viscocanalostomy, and a steering mechanism control device202 configured to control the steering of a steerable section 251 of theapplicator 201.

The steerable section 251 can be configured to deflect the distalstent-holding section 259 about at least one axis. Optionally, thesteerable section 251 can configured to deflect the distal stent-holdingsection 259 about at least two axes, one axis being substantiallyperpendicular to the other. Thus, the portion of the sheath 246 thatdefines part of the steerable section 251 is flexible. Generally,similar steering mechanisms for deflecting a portion of an medicaldevice, such as endoscopes, are well-known in the art.

With reference to FIG. 51B, in the illustrated embodiment, the steeringactuator 202 is connected to a plurality of pulling wires 256A, 256B.The wires 256A, 256B have distal portions 253A, 253B, respectively,disposed distally from the handle 205. The end 252A of the distal wireportion 253A of the first pulling wire 256A is attached to one side ofan inner surface of the sheath 246. The second pulling wire 256B has itsend 252B of the distal wire portion 253B attached to the opposite sideof the inner surface of the sheath 246. The wire ends 252A and 252B aredisposed within the steerable distal section 251.

With reference to FIG. 51C, a relatively rigid guide 254 is disposed inthe lumen at an appropriate location proximal to the wire ends 252A,252B. The guide is configured to guide the pull wires 256A, 256B suchthat the sheath 246 is deflected when the pull wires 256A, 256B arepulled. In the illustrated embodiment, the guide 254 is in the form of aplate member.

The guide 254 can include holes 255A, 255B through which the pullingwires 253A, 253B extend. The guide 254 and the points at which the wireends 252A, 25B are spaced. As such, when the pull wires 253A, 253B arepulled by actuation of the steering actuator 202, the distal end of thesheath 246 is deflected. For example, as shown in FIG. 51D, when thewire 256A is pulled, the sheath deflects from Position I to Position II.

As noted above, the delivery apparatus 201 can be configured todischarge a plurality of stents, one at a time, for implantation. In theillustrated embodiment, as shown in FIG. 51B, the delivery apparatus 201includes a plunger 244 connected with the stent delivery button 203. Theplunger 244 can comprise one or a plurality of plunger bodies that arejoined at the distal plunger end 244B. The distal plunger end 244B has agenerally round configuration and smooth surface adapted for evenlypushing a stent, such as the stent 229C, out of the sheath during adeployment phase of an implantation procedure.

As noted above, the sheath 246 defines a lumen 249 having a plunger 244.A space between the plunger 244 and the distal end 242 is reserved forstoring a plurality of stents. The sheath 246 includes at least oneholding member 245 for each stent 229C stored therein. The holdingmembers 245 are configured to retain the stents 229C in place duringstorage and use, and to allow the stents 229C to pass when the stent229C is pushed by the plunger 244.

In the illustrated embodiment, the sheath 146 includes a row of aplurality of holding members 245 upstream and downstream from each stent229C stored in the sheath 246. Thus, each stent 229C is prevented fromunintentionally moving in the upstream and downstream directions.

FIG. 51B illustrates two stents 229C being stored in the sheath 246.However, it is conceived that the sheath 246 and holding members 245 canbe configured to hold one, three, or more stents 229C within thestent-holding distal end 259.

The holding member 245 can be a wire configured to exerted a force tohold the stents 229C in place during storage and use, until the plunger244 is moved to discharge a stent 229C from the end 242. For example,the wire can be made from a spring metal, an elastically deformableplastic, or other material, sized and shaped to retain the stents 229Cduring storage, and to allow the stents 229C to pass under a force thatcan be generated by or applied to the plunger 244, toward the end 242.In the illustrated embodiment, the wires forming the holding members 245extend generally parallel to and convexly into the lumen 249, and thusdefine stops for preventing unintentional movement of the stents 229C.

Alternatively, the holding members 245 can be in the form of amechanically or electronically actuatable gate. Such a gate can beconfigured to move from a closed position in which the stents 229C areretained in the storage positions, and an open position in which thestents 229C can be moved in the downstream direction. A mechanical gatecan be formed from members that can be moved or deflected radially fromthe inner surface of the lumen 249, under the control of a pull wire(not shown). An electronic gate can also include radially movable ordeflectable members controlled by an electronic actuator, such as, forexample, but without limitation, solenoids, stepper motors, servomotors, and piezoelectric modules.

Alternatively, piezoelectric modules can be used to form the holdingmembers. For example, small piezoelectric modules can be mounted on theinner surface of the sheath 246 to form stops when in a locked position.The piezoelectric modules can be connected to a power supply withconduits. Thus, when actuated, the piezoelectric modules can contract soas to move to an open position in which the stents 229C can pass.

As noted above, the applicator 201 preferably is configured to eject onestent at a time from the end 242. Thus, the applicator 201 can beconfigured to move the plunger 244 a predetermined distance each timethe button 203 is depressed. For example, the button can be mechanicallyconnected to the plunger 244 so as to move the plunger 244 downstreamthrough the sheath 246 over the predetermined distance. Thepredetermined distance can be, for example, equal to about the length ofthe stent 229C.

Alternatively, the plunger can be driven by an electronic actuator (notshown) configured to eject one stent 229C at a time from the sheath 246.For example, the electronic actuator can be configured to drive theplunger 244 over the predetermined distance each time the button 203 isdepressed. The electronic actuator can be, for example but withoutlimitation, solenoids, stepper motors, servo motors, and piezoelectricmodules. Driver electronics (not shown) can be configured to drive theactuator so as to urge the plunger 244 over the predetermined distance.

Preferably, the end 242 of the sheath 246 is sharpened to define acutting (microtrephining) tip for creating a hole within the trabecularmeshwork 21 for stent placement. Thus, the applicator 201 can be usedfor cutting the trabecular meshwork 21 and for implanting stents.

A further advantage is provided where the applicator includes anillumination feature for illuminating at least a portion of theimplantation site. For example, the illumination feature can beconfigured to generally illuminate the site at which a stent is to beimplanted. Optionally, the illumination feature can be configured togenerate a reticule for aligning the applicator with the desiredimplantation site. In one embodiment, a light source is provided to thetip section 242 of the stent applicator 201 wherein either laser lightis provided for cutting/spotting or fiber optic light is provided forillumination.

For example, but without limitation, the illumination feature cancomprise a small diameter light pipe or optic fiber element configuredto emit a fine point or beam of light and configured to be introducedab-internally. Additionally, the face or lens of the pipe or element canbe configured to be placed against the trabecular meshwork. In oneembodiment, the light pipe or optic fiber is the construct material ofthe sheath 246 of the stent delivery applicator 241A for multiple stentdeployment as shown in FIG. 51B. In another embodiment, the light pipeor optic fiber is snugly inserted within the lumen 249 of the applicatorsheath 246 or over the outer periphery of the applicator sheath 246.Optionally, the illumination device can be configured such that thepoint or beam emitting from the light tube would be highly visible fromthe outside of the eye and serve to guide the implantation of a stent.

As an alternative to including an illumination feature with theapplicator 201, simple non-invasive trans-scleral illumination, if ofthe proper intensity and wavelength, perhaps in a darkened environment,could silhouette the Schlemm's canal, trabecular meshwork, or moreprobably, the scleral spur with sufficient resolution to enableab-externo placement of a device into Schlemm's canal. In this case,blood could be backed up in a retrograde manner into Schlemm's canal bythe surgeon to provide additional optical density. Imaging means for abinternally imaging the anatomic structures for TBS stent implantationusing ultrasound imaging, laser imaging, OCT imaging or multi-wavelengthscanning can also be provided.

A further advantage is provided where the applicator 201 also includesan imaging feature. For example, where the applicator 201 includes animaging feature for transmitting a video representation of animplantation site of a stent to a user of the applicator, animplantation procedure can be further simplified. The imaging featurecan utilize any type of known imaging techniques, including, forexample, but without limitation, optical, and ultrasonic. In oneembodiment, an endoscope is mounted at the tip section 242 of the stentapplicator 201 for visualization during stent deployment and/orimplantation.

FIG. 51D shows one embodiment of the applicator 201 of FIG. 51A havingan ultrasonic imaging system. The illustrated embodiment of the imagingsystem is included on an applicator with a steerable section. However,it is to be noted that the imaging system can be used on an applicatorthat does not have a steerable section.

In one embodiment, the ultrasonic imaging system comprises twoultrasonic probes or transducers 206, 207. The transducers 206, 207 canbe formed from an ultrasound ring or ultrasound tape. Preferably, thetransducers 206, 207 are located adjacent to the distal end 242 of thedelivery apparatus 201. As such, the transducers 206, 207 can move withthe distal end 242 during an implantation procedure.

The ultrasonic transducers 206, 207 are connected by flexible wires (notshown) through the interior void 243 of the apparatus or through withinthe sheath 246 to the connector 209 located at the handle 205 so thatthe ultrasonic signals are directed outwardly and received inwardlyrelative to the transducers 206, 207. For example, one of thetransducers 206, 207 can be configured to emit ultrasonic energy, andthe other can be configured to absorb the reflected portion of theemitted ultrasonic energy and to produce a signal indicative of theabsorbed energy.

In order to enhance the viewing and positioning of the distal end 242 ofthe apparatus, an ultrasonic marker 208, which is visible to ultrasonicenergy, can be mounted at about the distal end 242 of the applicator201. For example, but without limitation, such a marker 208 can be inthe form of one or a plurality of encapsulated air bubbles. In oneillustrative example, the bubble in a marker 208 can be formed byintroducing air by a syringe (not shown) penetrating the wall of thesheath 246 and thereafter sealing the hole created by the syringe withepoxy.

Optionally, a plurality of markers 208 can be disposed in the frontdistal section 259. The markers 208 can be sized and configured to aidin locating and identifying the orientation of the distal end section259. For example, the markers 208 can be located and/or viewed withexternal ultrasonic imaging systems (not shown), such as those commonlyused in similar medical procedures.

A further advantage is provided where the stent delivery applicator 201is both steerable and configured for multiple stent implantation. Assuch, the applicator 201 can be inserted into the anterior chamber 20,through an incision, such as a corneal incision, and multiple stents canthen be implanted at different locations without removing the applicator201 or creating other incisions, described in greater detail below.

FIG. 52A shows another embodiment of the stent delivery distal portion241, identified generally by the reference numeral 241B, and anotherembodiment of a stent, identified generally by the reference numeral229E.

The stent 229E comprises a first (proximal) flange 240E and a second(distal) flange 237E with a plurality of supporting legs or posts 236.The second flange 237E of the stent 229E is configured to be foldable.For example, the first flange 237E can be configured to be elasticallyfoldable toward an upstream direction. As such, the first flange 237Ecan be folded toward an upstream direction, as illustrated in FIG. 52Awhen stored in the sheath 246. Thus, after the first flange 237E hasbeen pushed through the end 242, the first flange 237E can resilientlyunfold. As such, the first flange 237E can provide enhanced anchoringfor the stent 229E when implanted into the trabecular meshwork 21.

A further advantage can be provided where the applicator 201 includes acutting device that can extend through the lumens 239E of the stents229E. For example, as shown in FIG. 52A, a cutting device 250 caninclude a cutting tip 247 and can be configured to extend through thestents 229E during an implantation procedure. As such, the cuttingdevice can being an incision at the center of the site at which thestent 229E is to be inserted through the trabecular meshwork 21. In theillustrated embodiment, the cutting device is in the form of a trocar.

With continued reference to FIG. 52A, the cutting device 250 isconfigured to be movable axially through the lumen 249 of the applicatorend portion 241B of the sheath 146. Additionally, the cutting device 250can be moved axially relative to the stent or stents through which itextends.

Another advantage can be provided where the cutting device 250 alsoincludes at least one holding member for holding a stent. For example,the cutting device 250 includes at least one holding device 245,described above with reference to FIG. 51B, can be configured to hold astent at least during an implantation procedure, and to release thestent at the appropriate time.

Preferably, the holding members 245B are arranged to align the sides ofthe cutting tip 247 with the distally facing sides of the flange 237Ewhen the flange 237E is folded. For example, as shown in FIG. 52A, whenthe flange 237E is folded, the distally facing side of the flange 237Eis aligned with the sides of the cutting tip 247, as indicated by thedashed-lines identified by the letter “A.” This alignment can befacilitated by arranging the holding members 245B such that the cuttingdevice 250 extends distally from the flange 237E sufficiently to causethe sides of the cutting tip 247 to become aligned with the flange 237E.As such, the sides of the cutting tip 247 and the distally facing sideof the flange 237E generate a more smooth surface for penetrating thetrabecular meshwork 21 during an implantation procedure.

During operation, the applicator end portion 241B can be pushed intotrabecular meshwork 21, with the flange 237E disposed in Schlemm's canal22, as shown in FIG. 52B. The sheath 246 can then be retracted out ofSchlemm's canal 22, leaving the cutting device 250 and stent 229E inplace (FIG. 52C).

With the sheath 246 retracted, the first flange 237E can unfold, asindicated by the arrows U in FIG. 52C, thereby providing enhancedanchoring of the stent 229E within Schlemm's canal 22 (FIG. 52D).Additionally, the second flange 240E is within the anterior chamber 20.

As shown in FIG. 52D, the cutting device 250 can then be retractedrelative to the applicator end portion 241B and the stent 229E, leavingthe stent 229E in place. Optionally, the cutting device 250 and thesheath 246 can be retracted together.

As noted above, the holding members 245 are configured to limit themovement of the stents 229E relative to the cutting device 250. When thecutting device is retracted, the next stent 229E preferably is movedpassed (in the downstream direction) the holding member 245 that waspreviously between the stents 229E. As such, the next stent 229E can bemoved into position for implantation. Thus, the holding members 245preferably are configured to allow the stent 229E to move toward thecutting tip 247 when the cutting device 250 is retracted. For example,the holding members 245 can be controlled so as to retract when thecutting device 250 is retracted.

With reference to FIG. 53, another embodiment of an axisymmetrictrabecular stenting device is illustrated therein and identifiedgenerally by the reference numeral 229F. For ease of description, butwithout limitation, the stent 229F is described below with reference tocylindrical coordinates of x, r and angle α as shown in FIG. 53.

The stent 229F comprises an inlet (proximal) section having a firstflange 240F, an outlet (distal) section having a second flange 237F anda middle section 284 connecting the inlet section and the outletsection. A lumen 239F of the device 229F is configured to transportaqueous, liquid, or therapeutic agents between the inlet section and theoutlet section. As referred to herein, “therapeutic agent” is intendedto include pharmaceutical agents, drugs, genes, cells, proteins, and/orgrowth factors.

The inlet section of the stent 229F has at least one inlet opening 286and the outlet section comprises at least one outlet opening 287. Afurther advantage is provided where the outlet section 237F includes atleast one opening 287, 288 suitably located for dischargingsubstantially axisymmetrically the aqueous, liquid or therapeuticagents, wherein the opening 287, 288 is in fluid communication with thelumen 285 of the device 281. In the illustrated embodiment, the openings288 extend radially from the lumen 285 and open at the outwardly facingsurface around the periphery of the outlet flange 237F.

In one embodiment of an implantation procedure, Pilocarpine isadministered preoperatively to constrict the pupil to provide maximalprotection of the lens in phakic individuals and to further open theanterior chamber angle to provide a better view of the surgical site.Topical and retrobulbar anesthetic are recommended. A small self-sealingtemporal corneal incision can be made and Healon® viscoelastic (VE) canbe injected to maintain the anterior chamber.

A microscope can be tilted slightly toward the surgeon and the patient'shead can be rotated away from the surgeon to provide a suitable view ofthe nasal trabecular meshwork using a direct-view gonioscope that isplaced on the eye. The applicator 201 with a preloaded stent, such as,for example, but without limitation, an one or any combination of thestents a plurality of any combination of the stents 229, 30, 30 a, 30 b,30 c, 30 d, 30 e, 30 f, 30 g, 30 h, 30 i, 30 j, 30 k, 30 m, 30 n, 30 p,30 q, 30 r, 30 s, 30 t, 30 u, 30 v, 229A, 229B, 229C, 229D, 229E, 229F,or any of the other stents described below, is advanced through thecorneal wound and across the anterior chamber. The stent is pushedagainst the trabecular meshwork and moved inferiorly to pierce thetrabecular meshwork and guide the stent into Schlemm's canal. Aftersuccessful implantation and release of the stent, the applicator iswithdrawn and the VE is flushed from the eye.

The G2 stent (for example, stent 229F of FIG. 53) can be smaller and ofa significantly different design than the G1 stents, thus allowing it tobe passed through a smaller corneal incision and be implanted with asimple axial motion. Reduced size and simplified surgical motions mayenable implantation of the G2 stent without the use of viscoelastic andtherefore eliminate a significant expendable material cost and the timenecessary to administer and remove it.

Additionally, viscoelastic use in patients undergoing eye surgery cancause post-operative transient IOP spikes that can further damage theremaining glaucoma-compromised retina. Reduced surgical manipulationsreduce the burden on the surgeon and reduce the stimulation andirritation of intraocular tissues. Furthermore, reduction in the cornealincision size raises the possibility that the incision could be made bythe G2 applicator, and could potentially reduce the surgical implantprocedure to an injectable implant procedure. Injectable stent therapyrepresents a potentially superior alternative to both end-stage surgicaltherapy and to patients burdened by the cumulative side effects,complications, and compliance issues associated with drug therapy.

The G2 stent and applicator system are sized, dimensioned and configuredfor placement through trabecular meshwork in an ab interno or ab externoprocedures. FIGS. 54A-C illustrate additional examples of preferred G2stent and applicator embodiments.

FIG. 54A shows yet another embodiment of a stent injector assembly formultiple stent deployment, identified generally by the reference numeral260. The stent injector 260 comprises a housing 261 with a distal cap262 and a distal stent-holding element 263 that is distal from thedistal cap 261. Optionally, at least a portion of the distalstent-holding element 263 can be configured to be steerable with asteering mechanism that can be constructed in accordance with thedescription of the steerable section 251 described above with referenceto FIGS. 51A-D.

The stent-holding element 263 can comprise an elongate member 264 withat least one stent slidably disposed thereon. The elongate member 264can be configured to extend through the lumen of any of the stents 229A,229B, 229C, 229D, 229E, 229F, or any of the other stents describedbelow.

In the illustrated embodiment, the elongate member 264 extends throughthe lumen of stents 229G (FIG. 54B). In one embodiment, the distal stent229G can be the same as the second or proximal stent 229G. In anotherembodiment, the distal stent and the proximal stent are different insize or configuration for placement at different locations. For example,the proximal and distal stents of FIG. 54B can be any combination of thestents 229A, 229B, 229C, 229D, 229E, 229F, and 229G. Additionally, theapplicator 260 can be configured to be loaded with only one, three, ormore stents.

In the illustrated embodiment, the distal flange 237G of the stent 229Gcan be wedge-shaped. For example, the distal end of the flange 237G canhave a smaller diameter than that of the proximal end of the flange237G. As such, the stent 229G can pass more easily through thetrabecular meshwork 21. Additionally, the distally facing surface of theflange 237G can be inclined so as to be aligned with a distal surface ofthe elongate member 264. As noted above with respect to the cuttingmember 250, the elongate member 264 can be in the form of a trocar.

The stent-holding element further comprises a sleeve 265 configured tosupport the elongate member 264. The sleeve 265 (for example, made ofhypo tubing) can be pressed or bonded onto the distal cap 262 to form asleeve-cap subassembly. The elongate member 264 can be configured to beaxially movable relative to the sleeve 265, as indicated by the arrow266 (FIG. 54C).

The housing 261 can also comprise a tip actuator 267 that has a distalend 268 and a proximal end 269. The elongate member 264 can be press fitor bonded into the distal end portion of the tip actuator 267 to form atip/tip actuator subassembly. In one exemplary but non-limitingembodiment, the elongate member 264 can be a 0.08 mm diameter sharpenedrod made from a hard material, such as a metal.

The tip/tip actuator subassembly is fed through the sleeve-capsubassembly and the cap 262 is screwed onto or bonded with the housing261. The proximal end 269 can include a threaded portion 270 adapted forthreaded engagement with a rotation knob 271 located at the proximal endportion of the housing 261. Thus, the coupling mechanism comprises thetip/tip-actuator subassembly screwed into the rotation knob 271 to forman actuator-knob subassembly.

An interlock arrangement 272 is configured to retain the knob 271 on thehousing 261 and allow the knob 271 to rotate relative to the housing261. The interlock arrangement 272 can include an annular rib disposedon the housing 261 and a groove disposed on the knob 271. A clearance isprovided between the groove and the rib so as to allow the knob 271 torotate freely relative to the housing 261. The knob 271 can be pressedonto the housing 261 and thus spins freely on housing 261 without comingoff because of an interlock arrangement 272.

With reference to FIGS. 54A and 54C, the housing 261 can include a slotline 273 at a location perpendicular to a longitudinal axis 275 of thehousing. One side of the slot line 273 can be drilled through to theopposite side of the housing, thus allowing an anti-rotation pin 274 toextend therethrough.

FIG. 54C shows a top cross-sectional view, identified as section 3-3 ofFIG. 54A, with the anti-rotation pin 274 aligned with the slot 276.During assembly, of the injector 260, the tip actuator 267 is rotateduntil the slot 276 is aligned with the drilled hole adapted for theanti-rotation pin 274 to extend into the drilled hole. The anti-rotationpin 274 is pressed through a first side of housing, through the tipactuator, and through a second opposite side of housing.

In operation, one or more stents are placed over the member 264 andagainst the blunt front end of the sleeve 265. After the injectorapproaches the target site, the elongate member 264 and the first stentare pressed into tissue where implantation is to take place. In an abinterno procedure, the first tissue is the trabecular meshwork facingthe anterior chamber. In an ab externo procedure, the first tissue isthe trabecular meshwork facing Schlemm's canal. Once the first stent isin a proper location, the knob 271 is rotated to withdraw the elongatemember 264, leaving the first stent in place. Stents can be snugly heldonto the tip 264 with a mechanical feature on the elongate member, suchas the holding members 245 described above with reference to FIGS.51A-D. Optionally, the sleeve 265 can include a mechanical feature forholding stents in place. Further viscoelastic material or other meanscan be provided for holding the stents so that stent deployment does notoccur until desired.

FIG. 55 shows an embodiment of the seton implant 331 constructedaccording to the principles of the invention. The seton implant maycomprise a biocompatible material, such as a medical grade silicone, forexample, the material sold under the trademark Silastic™, which isavailable from Dow Corning Corporation of Midland, Mich., orpolyurethane, which is sold under the trademark Pellethane™, which isalso available from Dow Corning Corporation. In an alternate embodiment,other biocompatible materials (biomaterials) may be used, such aspolyvinyl alcohol, polyvinyl pyrrolidone, collagen, heparinizedcollagen, tetrafluoroethylene, fluorinated polymer, fluorinatedelastomer, flexible fused silica, polyolefin, polyester, polysilicon,mixture of biocompatible materials, and the like. In a further alternateembodiment, a composite biocompatible material by surface coating theabove-mentioned biomaterial may be used, wherein the coating materialmay be selected from the group consisting of polytetrafluoroethylene(PTFE), polyimide, hydrogel, heparin, therapeutic drugs, and the like.

The main purpose of the seton implant is to assist in facilitating theoutflow of aqueous in an outward direction 340 into the Schlemm's canaland subsequently into the aqueous collectors and the aqueous veins sothat the intraocular pressure is balanced. In one embodiment, the setonimplant 331 comprises an elongated tubular element having a distalsection 332 and an inlet section 344. A rigid or flexible distal section332 is positioned inside one of the existing outflow pathways. Thedistal section may have either a tapered outlet end 333 or have at leastone ridge 337 or other retention device protruding radially outwardlyfor stabilizing the seton implant inside the existing outflow pathwaysafter implantation. For stabilization purposes, the outer surface of thedistal section 332 may comprise a stubbed surface, a ribbed surface, asurface with pillars, a textured surface, or the like. The outer surface336, including the outer region 335 and inner region 334 at the outletend 333, of the seton implant is biocompatible and tissue compatible sothat the interaction/irritation between the outer surface and thesurrounding tissue is minimized. The seton implant may comprise at leastone opening at a location proximal the distal section 332, away from theoutlet end 333, to allow flow of aqueous in more than one direction. Theat least one opening may be located on the distal section 332 at aboutopposite of the outlet end 333.

In another exemplary embodiment, the seton implant 331 may have aone-way flow controlling means 339 for allowing one-way aqueous flow340. The one-way flow controlling means 339 may be selected from thegroup consisting of a check valve, a slit valve, a micropump, asemi-permeable membrane, or the like. To enhance the outflow efficiency,at least one optional opening 341 in the proximal portion of the distalsection 332, at a location away from the outlet end 333, and in anexemplary embodiment at the opposite end of the outlet end 333, isprovided.

FIG. 56 shows a top cross-sectional view of FIG. 55. The shape of theopening of the outlet end 333 and the remaining body of the distalsection 332 may be oval, round or some other shape adapted to conform tothe shape of the existing outflow pathways. This configuration willmatch the contour of Schlemm's canal to stabilize the inlet section withrespect to the iris and cornea by preventing rotation.

As shown in FIG. 55, the seton implant of the present invention may havea length between about 0.5 mm to over a meter, depending on the bodycavity the seton implant applies to. The outside diameter of the setonimplant may range from about 30 μm to about 500 μm. The lumen diameteris preferably in the range between about 20 μm to about 150 μm. Theseton implant may have a plurality of lumens to facilitate multiple flowtransportation. The distal section may be curved at an angle betweenabout 30 degrees to about 150 degrees, in an exemplary embodiment ataround 70-110 degrees, with reference to the inlet section 344.

FIG. 57 shows another embodiment of the seton implant 345 constructed inaccordance with the principles of the invention. In an exemplaryembodiment, the seton implant 345 may comprise at least two sections: aninlet section 347 and an outlet section 346. The outlet section has anoutlet opening 48 that is at the outlet end of the seton implant 345.The shape of the outlet opening 348 is preferably an oval shape toconform to the contour of the existing outflow pathways. A portion ofthe inlet section 347 adjacent the joint region to the outlet section346 will be positioned essentially through the diseased trabecularmeshwork while the remainder of the inlet section 347 and the outletsection 346 are outside the trabecular meshwork. As shown in FIG. 5, thelong axis of the oval shape opening 348 lies in a first plane formed byan X-axis and a Y-axis. To better conform to the anatomical contour ofthe anterior chamber 20, the trabecular meshwork 21 and the existingoutflow pathways, the inlet section 347 may preferably lie at anelevated second plane, at an angle θ, from the first plane formed by animaginary inlet section 347A and the outlet section 346. The angle θ maybe between about 30 degrees and about 150 degrees.

After the first stent is implanted, the injector is slightly withdrawnaway from the trabecular meshwork. The tip of the injector is moved andpointed to a second target site without withdrawing the injector fromthe incision on the sclera. This re-positioning of the injector can beaccomplished with a steerable section of the injector 260 noted above.

The term “targeted placement” of trabecular stents refers to theintentional placement of a stent at a particular location in Schlemm'scanal for the purpose of providing a maximum benefit in the form ofmaximum outflow facility. With reference to FIG. 50A, aqueous entersSchlemm's canal 22 through the trabecular meshwork 21 and travels alongthe canal to exit through the collector channels 23. Schlemm's canal isa narrow channel with approximate dimensions of 250 μm×20 μm with a 40mm length (Volume˜0.2 μl) and it provides measurable resistance to theflow of aqueous. Therefore, placing a stent into Schlemm's canal 22through the trabecular meshwork 21 yields the best improvement inoutflow facility when it is placed near a large collector channel 23 ora group of smaller ones that combine to have a larger hydraulicdiameter. It is one aspect of the present invention to locate/detect themost appropriate collector channel(s) to implant a trabecular shuntingstent adjacent the collector channel(s) 23.

The term “Multi-stent therapy” refers to the intentional placement of astent in each of several locations in Schlemm's canal 22. SinceSchlemm's canal 22 has measurable resistance to flow at physiologicalflow rates, a plurality of stents is strategically placed close toconcentrations of collector ducts 23 or a large collector anddistributed around Schlemm's canal 22 to maximize the impact of multiplestents.

An injector or device applicator to hold a plurality of serial deviceshas advantages of placing the device one at a time without reloading thedevice or without completely withdrawing the applicator out of a portionof the body. The advantages may include saving operating time, reducingredundant incision or injury, or exact positioning for device placement.

By way of example, but without limitation, an injector or deviceapplicator for multiple device deployment may be used for implantingpunctum plugs in an eye, for implanting drug-eluting devices into scleratissue of an eye, implanting drug-eluting devices into tissue of aposterior segment, or implanting cardiovascular stents. Some aspects ofat least one of the inventions disclosed herein relate to a method ofmultiple device deployment comprising: (a) loading a plurality ofdevices within a device-retaining space of a device applicator; (b)delivering the applicator to a first target implant site; (c) deployinga first device at the first target implant site; (d) detaching theapplicator from the first target implant site; (e) directing theapplicator to a second target implant site; (f) deploying a seconddevice at the second target implant site; and (g) withdrawing theapplicator.

The device of the exemplary embodiment preferably comprises abiocompatible material such that inflammation arising due to irritationbetween the outer surface of the device and the surrounding tissue isminimized. Biocompatible materials which may be used for the device 81preferably include, but are not limited to, titanium, titanium alloys,polypropylene, nylon, PMMA (polymethyl methacrylate), medical gradesilicone, e.g., Silastic™, available from Dow Coming Corporation ofMidland, Mich.; and polyurethane, e.g., Pellethane™, also available fromDow Corning Corporation.

In other embodiments, the device of the embodiments may comprise othertypes of biocompatible material, such as, by way of example, polyvinylalcohol, polyvinyl pyrrolidone, collagen, heparinized collagen,polytetrafluoroethylene, expanded polytetrafluoroethylene, fluorinatedpolymer, fluorinated elastomer, flexible fused silica, polyolefin,polyester, polysilicon, and/or a mixture of the aforementionedbiocompatible materials, and the like. In still other embodiments,composite biocompatible material may be used, wherein a surface materialmay be used in addition to one or more of the aforementioned materials.For example, such a surface material may include polytetrafluoroethylene(PTFE) (such as Teflon™), polyimide, hydrogel, heparin, therapeuticdrugs (such as beta-adrenergic antagonists and other anti-glaucomadrugs, or antibiotics), and the like.

FIG. 58 illustrates a preferred embodiment of a trabecularshunting/stenting device 431, which facilitates the outflow of aqueousfrom the anterior chamber 20 into Schlemm's canal 22, and subsequentlyinto the aqueous collectors and the aqueous veins so that intraocularpressure is reduced. In the illustrated embodiment, the trabecularstenting device 431 comprises an inlet section 402, having an inletopening 403, a middle section 404, and an outlet section 409. The middlesection 404 may be an extension of, or may be coextensive with, theinlet section 402. The outlet section 409 is preferably somewhatflexible to facilitate positioning of the outlet section 409 within anoutflow pathway of the eye 10. The outlet section 409 is preferablysubstantially perpendicular to the middle section 404. “Substantiallyperpendicular,” as used herein, is defined as subtending an anglebetween longitudinal axes of the sections 404, 409 ranging between about30 degrees and about 150 degrees. The device 431 further comprises atleast one lumen 407 within sections 404 and 409 which is in fluidcommunication with the inlet opening 403 of section 402, therebyfacilitating transfer of aqueous through the device 431.

In one embodiment, the outlet section 409 has at least one outlet end.In another embodiment, the outlet section preferably has a first outletend 406 and a second, opposite outlet end 405. The lumen 407 within theoutlet section 409 opens to at least one of the outlet ends 405, 406.Furthermore, the outlet section 409 may have a plurality of sideopenings 477, each of which is in fluid communication with the lumen407, for transmission of aqueous. The middle section 404 is connected toor coextensive with the outlet section 409 and is disposed between thefirst outlet end 406 and the second outlet end 405. In a preferredembodiment, the outlet section 409 is curved around a point, or a curvecenter, and the middle section 404 extends substantially along a planethat contains the curve center. In this embodiment, the outlet section409 has a radius of curvature ranging between about 4 mm and about 10mm.

As will be apparent to a person skilled in the art, the lumen 407 andthe remaining body of the outlet section 409 may have a cross-sectionalshape that is oval, circular, or other appropriate shape. Thecross-sectional shapes of the lumen 407 and the outlet section 409preferably conform to the shape of the outflow pathway into which theoutlet section 409 is placed. The opening of the lumen 407 of the outletends 405, 406 may be ovoid in shape to match the contour of Schlemm'scanal 22. Further, an outer contour of the outlet section 409 may beelliptical (e.g., ovoid) in shape to match the contour of Schlemm'scanal 22. This serves to minimize rotational movement of the outletsection 409 within Schlemm's canal 22, and thereby stabilizes the inletsection 402 with respect to the iris and cornea.

A circumferential ridge 408 is provided at the junction of the inletsection 402 and the middle section 404 to facilitate stabilization ofthe device 431 once implanted within the eye 10. Preferably, the middlesection 404 has a length (between the ridge 408 and the outlet section409) that is roughly equal to a thickness of the trabecular meshwork 21,which typically ranges between about 100 μm and about 300 μm. Inaddition, the outlet section 409 may advantageously be formed with aprotuberance or spur projecting therefrom so as to further stabilize thedevice 431 within the eye 10 without undue suturing.

FIG. 63 is a close-up view of the inlet section 402 of the trabecularstenting device 431, illustrating a flow-restricting member 472, whichis tightly retained within a lumen 478. The flow-restricting member 472is shown located close to an inlet side 471 of the inlet section 402.The flow-restricting member 472 serves to selectively restrict at leastone component in blood from moving retrograde, i.e., from the outletsection 409 into the anterior chamber 20 of the eye 10. Alternatively,the flow-restricting member 472 may be situated in any location withinthe device 431 such that blood flow is restricted from retrogrademotion. The flow-restricting member 472 may, in other embodiments, be afilter made of a material selected from the following filter materials:expanded polytetrafluoroethylene, cellulose, ceramic, glass, Nylon,plastic, and fluorinated material such as polyvinylidene fluoride(“PVDF”) (trade name: Kynar, by DuPont).

The trabecular stenting device 431 may be made by molding,thermo-forming, or other micro-machining techniques. The trabecularstenting device 431 preferably comprises a biocompatible material suchthat inflammation arising due to irritation between the outer surface ofthe device 431 and the surrounding tissue is minimized. Biocompatiblematerials which may be used for the device 431 preferably include, butare not limited to, titanium, medical grade silicone, e.g., Silastic™,available from Dow Coming Corporation of Midland, Mich.; andpolyurethane, e.g., Pellethane™, also available from Dow CorningCorporation. In other embodiments, the device 431 may comprise othertypes of biocompatible material, such as, by way of example, polyvinylalcohol, polyvinyl pyrrolidone, collagen, heparinized collagen,polytetrafluoroethylene, expanded polytetrafluoroethylene, fluorinatedpolymer, fluorinated elastomer, flexible fused silica, polyolefin,polyester, polysilicon, and/or a mixture of the aforementionedbiocompatible materials, and the like. In still other embodiments,composite biocompatible material may be used, wherein a surface materialmay be used in addition to one or more of the aforementioned materials.For example, such a surface material may include polytetrafluoroethylene(PTFE) (such as Teflon™), polyimide, hydrogel, heparin, therapeuticdrugs (such as beta-adrenergic antagonists and other anti-glaucomadrugs, or antibiotics), and the like.

As is well known in the art, a device coated or loaded with aslow-release substance can have prolonged effects on local tissuesurrounding the device. The slow-release delivery can be designed suchthat an effective amount of substance is released over a desiredduration. “Substance,” as used herein, is defined as any therapeutic orbioactive drug or agents that can stop, mitigate, slow-down or reverseundesired disease processes.

In one embodiment, the device 431 may be made of a biodegradable (alsoincluding bioerodible) material admixed with a substance for substanceslow-release into ocular tissues. In another embodiment, polymer filmsmay function as substance containing release devices whereby the polymerfilms may be coupled or secured to the device 431. The polymer films maybe designed to permit the controlled release of the substance at achosen rate and for a selected duration, which may also be episodic orperiodic. Such polymer films may be synthesized such that the substanceis bound to the surface or resides within a pore in the film so that thesubstance is relatively protected from enzymatic attack. The polymerfilms may also be modified to alter their hydrophilicity, hydrophobicityand vulnerability to platelet adhesion and enzymatic attack. In oneembodiment, the polymer film is made of biodegradable material.

Furthermore, the film may be coupled (locally or remotely) to a powersource such that when substance delivery is desired, a brief pulse ofcurrent is provided to alter the potential on the film to cause therelease of a particular amount of the substance for a chosen duration.Application of current causes release of a substance from the surface ofthe film or from an interior location in the film such as within a pore.The rate of substance delivery is altered depending on the degree ofsubstance loading on the film, the voltage applied to the film, and bymodifying the chemical synthesis of substance delivery polymer film.

The power-activated substance delivery polymer film may be designed tobe activated by an electromagnetic field, such as, by way of example,NMR, MRI, or short range RF transmission (such as a Bluetooth®apparatus). In addition, ultrasound can be used to cause a release of aparticular amount of substance for a chosen duration. This isparticularly applicable to a substance coated device or a device made ofa substrate containing the desired substance.

The device 431 may be used for a direct release of pharmaceuticalpreparations into ocular tissues. As discussed above, thepharmaceuticals may be compounded within the device 431 or form acoating on the device 431. Any known drug therapy for glaucoma may beutilized, including but not limited to, the following:

U.S. Pat. No. 6,274,138, issued Aug. 14, 2001, and U.S. Pat. No.6,231,853, issued May 15, 2001, the entire contents of both of which areincorporated herein by reference, disclose the function of mitochondriaand toxic substances synthesized as a metabolic byproduct withinmitochondria of cells. Perry and associates (Perry HD et al. “Topicalcyclosporin A in the management of postkeratoplasty glaucoma” Cornea16:284-288, 1997) report that topical cyclosporin-A has been shown toreduce post-surgical increases in intraocular pressure. It is proposedthat such compounds with known effects on mitochondrial stability mightbe effective in treating trabecular meshwork. An antagonistic drug toneutralize the toxic byproduct or a stabilizing drug to effectmitochondrial stability is believed able to restore the mitochondriafunction and subsequently mitigate the dysfunction of the trabecularmeshwork.

U.S. Pat. No. 6,201,001, issued Mar. 13, 2001, the entire contents ofwhich are incorporated herein by reference, discloses Imidazoleantiproliferative agents useful for neovascular glaucoma.

U.S. Pat. No. 6,228,873, issued May 8, 2001, the entire contents ofwhich are incorporated herein by reference, discloses a new class ofcompounds that inhibit function of sodium chloride transport in thethick ascending limb of the loop of Henle, wherein the preferredcompounds useful are furosemide, piretanide, benzmetanide, bumetanide,torasernide and derivatives thereof

U.S. Pat. No. 6,194,415, issued Feb. 27, 2001, the entire contents ofwhich are incorporated herein by reference, discloses a method of usingquinoxalines (2-imidazolin-2-ylamino) in treating neural injuries (e.g.,glaucomatous nerve damage).

U.S. Pat. No. 6,060,463, issued May 9, 2000, and U.S. Pat. No.5,869,468, issued Feb. 9, 1999, the entire contents of which areincorporated herein by reference, disclose treatment of conditions ofabnormally increased intraocular pressure by administration ofphosphonylmethoxyalkyl nucleotide analogs and related nucleotideanalogs.

U.S. Pat. No. 5,925,342, issued Jul. 20, 1999, the entire contents ofwhich are incorporated herein by reference, discloses a method forreducing intraocular pressure by administration of potassium channelblockers.

U.S. Pat. No. 5,814,620, issued Sep. 29, 1998, the entire contents ofwhich are incorporated herein by reference, discloses a method ofreducing neovascularization and of treating various disorders associatedwith neovascularization. These methods include administering to a tissueor subject a synthetic oligonucleotide.

U.S. Pat. No. 5,767,079, issued Jun. 16, 1998, the entire contents ofwhich are incorporated herein by reference, discloses a method fortreatment of ophthalmic disorders by applying an effective amount ofTransforming Growth Factor-Beta (TGF-beta) to the affected region.

U.S. Pat. No. 5,663,205, issued Sep. 2, 1997, the entire contents ofwhich are incorporated herein by reference, discloses a pharmaceuticalcomposition for use in glaucoma treatment which contains an activeingredient5-[1-hydroxy-2-[2-(2-methoxyphenoxyl)ethylamino]ethyl]-2-methylbenzenesulfonamide.This agent is free from side effects, and stable and has an excellentintraocular pressure reducing activity at its low concentrations, thusbeing useful as a pharmaceutical composition for use in glaucomatreatment.

U.S. Pat. No. 5,652,236, issued Jul. 29, 1997, the entire contents ofwhich are incorporated herein by reference, discloses pharmaceuticalcompositions and a method for treating glaucoma and/or ocularhypertension in the mammalian eye by administering thereto apharmaceutical composition which contains as the active ingredient oneor more compounds having guanylate cyclase inhibition activity. Examplesof guanylate cyclase inhibitors utilized in the pharmaceuticalcomposition and method of treatment are methylene blue, butylatedhydroxyanisole and N-methylhydroxylamine.

U.S. Pat. No. 5,547,993, issued Aug. 20, 1996, the entire contents ofwhich are incorporated herein by reference, discloses that2-(4methylaminobutoxy) diphenylmethane or a hydrate or pharmaceuticallyacceptable salt thereof have been found useful for treating glaucoma.

U.S. Pat. No. 5,502,052, issued Mar. 26, 1996, the entire contents ofwhich are incorporated herein by reference, discloses use of acombination of apraclonidine and timolol to control intraocularpressure. The compositions contain a combination of an alpha-2 agonist(e.g., para-amino clonidine) and a beta blocker (e.g., betaxolol).

U.S. Pat. No. 6,184,250, issued Feb. 6, 2001, the entire contents ofwhich are incorporated herein by reference, discloses use ofcloprostenol and fluprostenol analogues to treat glaucoma and ocularhypertension. The method comprises topically administering to anaffected eye a composition comprising a therapeutically effective amountof a combination of a first compound selected from the group consistingof beta-blockers, carbonic anhydrase inhibitors, adrenergic agonists,and cholinergic agonists, together with a second compound.

U.S. Pat. No. 6,159,458, issued Dec. 12, 2000, the entire contents ofwhich are incorporated herein by reference, discloses an ophthalmiccomposition that provides sustained release of a water solublemedicament formed by comprising a crosslinked carboxy-containingpolymer, a medicament, a sugar and water.

U.S. Pat. No. 6,110,912, issued Aug. 29, 2000, the entire contents ofwhich are incorporated herein by reference, discloses methods for thetreatment of glaucoma by administering an ophthalmic preparationcomprising an effective amount of a non-corneotoxic serine-threoninekinase inhibitor, thereby enhancing aqueous outflow in the eye andtreatment of the glaucoma. In some embodiments, the method ofadministration is topical, whereas it is intracameral in otherembodiments. In still further embodiments, the method of administrationis intracanalicular.

U.S. Pat. No. 6,177,427, issued Jan. 23, 2001, the entire contents ofwhich are incorporated herein by reference, discloses compositions ofnon-steroidal glucocorticoid antagonists for treating glaucoma or ocularhypertension.

U.S. Pat. No. 5,952,378, issued Sep. 14, 1999, the entire contents ofwhich are incorporated herein by reference, discloses the use ofprostaglandins for enhancing the delivery of drugs through theuveoscleral route to the optic nerve head for treatment of glaucoma orother diseases of the optic nerve as well as surrounding tissue. Themethod for enhancing the delivery to the optic nerve head comprisescontacting a therapeutically effective amount of a compositioncontaining one or more prostaglandins and one or more drug substanceswith the eye at certain intervals.

FIG. 59 illustrates another embodiment of a trabecular stenting device431A that facilitates the outflow of aqueous from the anterior chamber20 into Schlemm's canal 22, and subsequently into the aqueous collectorsand the aqueous veins so that intraocular pressure is reduced. Thedevice 431A comprises an inlet section 402A, a middle section 404A, andan outlet section 409A. The device 431A further comprises at least onelumen 403A traversing the sections 402A, 404A, 409A and providing fluidcommunication therebetween. The lumen 403A facilitates the transfer ofaqueous from the inlet section 402A through the device 431A. The outletsection 409A is preferably curved, and may also be somewhat flexible, tofacilitate positioning of the outlet section 409A within an existingoutflow pathway of the eye 10. The outlet section 409A may furthercomprise an elongate trough 7A for transmitting, or venting, aqueous.The elongate trough 7A is connected to and in fluid communication withthe lumen 403A within the trabecular stenting device 431A.

A circumferential ridge 8A is provided at the junction of the inletsection 402A and the middle section 404A to facilitate stabilization ofthe device 431A once implanted within the eye 10. Preferably, the middlesection 404A has a length (between the ridge 8A and the outlet section409A) that is roughly equal to the thickness of the trabecular meshwork21, which typically ranges between about 100 μm and about 300 μm. Inaddition, the outlet section 409A may advantageously be formed with aprotuberance or barb projecting therefrom so as to further stabilize thedevice 431A within the eye 10 without undue suturing.

As will be appreciated by those of ordinary skill in the art, thedevices 431 and 431A may advantageously be practiced with a variety ofsizes and shapes without departing from the scope of the invention.Depending upon the distance between the anterior chamber 20 and thedrainage vessel (e.g., a vein) contemplated, the devices 431, 431A mayhave a length ranging from about 0.05 centimeters to over 10centimeters. Preferably, the devices 431 and 431A have an outsidediameter ranging between about 30 μm and about 500 μm, with the lumens407, 403A having diameters ranging between about 20 μm and about 250 μm,respectively. In addition, the devices 431, 431A may have a plurality oflumens to facilitate transmission of multiple flows of aqueous. Theinlet sections 402, 402A have longitudinal axes that form an angle (θ)ranging between about 20 degrees and about 150 degrees relative to thelongitudinal axes of the middle sections 404, 404A, respectively. Morepreferably, the angles between the longitudinal axes of the inletsections 402, 402A and the middle sections 404, 404A range between about30 degrees and about 60 degrees, respectively.

One preferred method for increasing aqueous outflow in the eye 10 of apatient, to reduce intraocular pressure therein, comprises bypassing thetrabecular meshwork 21. In operation, the middle section 404 of thedevice 431 is advantageously placed across the trabecular meshwork 21through a slit or opening. This opening can be created by use of alaser, a knife, or other surgical cutting instrument. The opening mayadvantageously be substantially horizontal, i.e., extendinglongitudinally in the same direction as the circumference of the limbus15. Other opening directions may also be used, as well. The opening mayadvantageously be oriented at any angle, relative to the circumferenceof the limbus 15, that is appropriate for inserting the device 431through the trabecular meshwork 21 and into Schlemm's canal 22 or otheroutflow pathway, as will be apparent to those skilled in the art. Themiddle section 404 may be semi-flexible and/or adjustable in positionrelative to the inlet section 402 and/or the outlet section 409, furtheradapting the device 431 for simple and safe glaucoma implantation.Furthermore, the outlet section 409 may be positioned into fluidcollection channels of the natural outflow pathways. Such naturaloutflow pathways include Schlemm's canal 22, aqueous collector channels,aqueous veins, and episcleral veins. The outlet section 409 may bepositioned into fluid collection channels up to at least the level ofthe aqueous veins, with the device inserted in a retrograde or antegradefashion.

FIG. 60 generally illustrates a step in the implantation of thetrabecular stenting device 431 through the trabecular meshwork 21. Theoutlet section 409 of the device 431 is inserted into an opening 61 inthe trabecular meshwork 21. A practitioner may create the opening 61 “abinterno” from the interior surface 65 of the trabecular meshwork 21. Thepractitioner then advances the first outlet end 406 of the outletsection 409 through the opening 61 into a first side of Schlemm's canal22 or other suitable outflow pathway within the eye 10. Next, thepractitioner advances the second outlet end 405 through the opening 61and into a second side of Schlemm's canal 22. The advancing of thesecond outlet end 405 may be facilitated by slightly pushing the secondoutlet end 405 through the opening 61.

FIG. 62 generally illustrates a further stage in deployment of thedevice 31, wherein the entire outlet section 409 of the device 431 isimplanted within Schlemm's canal 22, beneath the trabecular meshwork 21.At this stage, the lumen 403 of the implanted device 431 provides anenhanced fluid communication through the trabecular meshwork 21.

FIG. 61 shows an additional and/or alternate step in the implantation ofthe trabecular stenting device 431 through the trabecular meshwork 21.The practitioner inserts a distal end 463 of a guidewire 464 through theopening 61 into the first side of Schlemm's canal 22. The practitionerthen advances the first outlet end 406 of the outlet section 409 intoSchlemm's canal 22 by “riding,” or advancing, the trabecular stentingdevice 431 on the guidewire 464. As will be apparent to those skilled inthe art, the guidewire 464 will have a shape and size conforming to theshape and size of the lumen 7; and as such, may have an elliptical(e.g., oval) shape, a D-shape, a round shape, or an irregular(asymmetric) shape which is adapted for nonrotatory engagement for thedevice 31.

Another method for increasing aqueous outflow within the eye 10 of apatient, and thus reduce intraocular pressure therein, comprises: (a)creating an opening in the trabecular meshwork 21, wherein thetrabecular meshwork 21 includes a deep side and superficial side; (b)inserting the trabecular stenting device 431 into the opening; and (c)transmitting aqueous through the device 31, to bypass the trabecularmeshwork 21, from the deep side to the superficial side of thetrabecular meshwork 21. This “transmitting” of aqueous is preferablypassive, i.e., aqueous flows out of the anterior chamber 20 due to apressure gradient between the anterior chamber 20 and the aqueous venoussystem 23.

Another method for increasing aqueous outflow within the eye 10 of apatient, and thus reduce intraocular pressure therein, comprises a)providing at least one bioactive substance incorporated into atrabecular stenting device at about the middle section of the device; b)implanting the trabecular stenting device within a trabecular meshworkof an eye such that the middle section is configured substantiallywithin the trabecular meshwork, the stenting device having a first endpositioned in an anterior chamber of the eye while a second end ispositioned inside a Schlemm's canal, wherein the first and the secondends of the trabecular stenting device establish a fluid communicationbetween the anterior chamber and the Schlemm's canal; and c) allowingthe middle section of the trabecular stenting device to release aquantity of the bioactive substance into the trabecular meshwork. Inanother embodiment, the at least one bioactive substance or agent isincorporated into the device at about the outlet section for releasingthe bioactive agent into Schlemm's canal and/or downstream of Schlemm'scanal.

It should be understood that the devices 431 and 31A are in now waylimited to implantation within only Schlemm's canal 20, as depicted inFIGS. 60 and 61. Rather, the devices 31 and 431A may advantageously beimplanted within and/or used in conjunction with a variety of othernatural outflow pathways, or biological tubular structures, as mentionedabove. As will be apparent to those of ordinary skill in the art, thedevices 431 and 431A may advantageously be used in conjunction withsubstantially any biological tubular structure without detracting fromthe scope of the invention.

FIG. 64 shows one embodiment of an axisymmetric trabecular stentingdevice 481 according to the principles of the invention. An axisymmetricdevice 481 has a coordination of x, r and angle α as shown in FIG. 64,rather than depending on a conventional coordination of x, y, and z. Thedevice 481 comprises an inlet (proximal) section 482, an outlet (distal)section 483 and a middle section 484 connecting the inlet section 482and the outlet section 483. A lumen 485 of the device 481 is fortransporting aqueous, liquid, or therapeutic agents between the inletsection and the outlet section, wherein the therapeutic agent is hereinintended to include pharmaceutical agents, drugs, genes, cells, and/orgrowth factors. The inlet section 482 has at least one inlet opening 486while the outlet section 483 comprises at least one outlet opening 487.In some aspect, the outlet section 483 may comprise a plurality ofopenings 487, 488 suitably located for outletting axisymmetrically theaqueous, liquid or therapeutic agents, wherein each of the openings 488is in fluid communication with the lumen 485 of the device 481.

In one embodiment, at least one bioactive agent is loaded onto theexterior surface or into the pores of the exterior surface of the middlesection 404, 484 of the stenting device 431, 481 enabling releasing intothe trabecular meshwork upon device implantation. In general, thebioactive agents may comprise pharmaceutical agents, drugs, genes,cells, and/or growth factors. In some aspect, at least some bioactiveagents may be loaded onto the inner surface or into the pores of theinner surface of the middle section of the stenting devices. In still afurther aspect, the middle section 404, 484 may be constructed of porousmaterial enabling the loaded therapeutic agents controllably releasingto the desired surrounding tissue, wherein the therapeutic agents arediffusible through the pores. Preferably, the middle section 484 has alength (between the inlet section 482 and the outlet section 483) thatis roughly equal to a thickness of the trabecular meshwork 21, whichtypically ranges between about 100 μm and about 300 μm.

Some aspects of the invention provide a stent with at least onebioactive agent being loaded onto the exterior surface or into the poresof the exterior surface of the outlet section 409, 483 of the stentingdevice 431, 481 enabling releasing into Schlemm's canal or collectorchannels upon device implantation.

To further stenting Schlemm's canal after implanting the device 481, aplurality of elevated (that is, protruding axially) supports or pillars489 is located at the distal-most end of the outlet section 483 sizedand configured for allowing media (for example, aqueous, liquid,balanced salt solution, viscoelastic fluid, therapeutic agents, or thelike) to be transported freely. Some aspects of the invention relate tothe device 481 having a plurality of elevated (that is, protrudingaxially) supports or pillars 489 that are made of biodegradable materialmixed with at least one bioactive agent. Once implanted, the bioactiveagent is slowly released from the biodegradable supports 489 to treatthe Schlemm's canal tissue.

In a further aspect, a plurality of the stenting device 481 is loaded ina cartridge to be inserted into a loading chamber of a device deliveryapplicator 451 or directly loaded inside the loading chamber of a devicedelivery applicator 451 enabling for multiple stents implantation. Inthis method, the distal end of the applicator 451 is movably positionedfrom one location at the trabecular meshwork after implanting a firststent to another location of the trabecular meshwork for implanting asecond stent and so forth without withdrawing the applicator out of theanterior chamber of the eye.

Some aspects of the invention provide the device 431, 481 adapted for adirect release of at least one bioactive agent for treating oculartissues. As discussed above, the bioactive or therapeutic agents may becompounded within the device 431, 481 or form a coating on the device431, 481. Any known drug or non-drug therapeutic agents for glaucoma maybe utilized, including but not limited to, the following:

U.S. Pat. No. 6,436,703, issued Aug. 20, 2002, the entire contents ofwhich are incorporated herein by reference, discloses a method andcompositions comprising novel isolated polypeptides, novel isolatedpolynucleotides encoding such polypeptides, including recombinant DNAmolecules, cloned genes or degenerate variants thereof, especiallynaturally occurring variants such as allelic variants, antisensepolynucleotide molecules, and antibodies that specifically recognize oneor more epitopes present on such polypeptides, as well as hybridomasproducing such antibodies. The compositions in '703 additionally includevectors, including expression vectors, containing the polynucleotides ofthe invention, cells genetically engineered to contain suchpolynucleotides and cells genetically engineered to express suchpolynucleotides, any of which might be effective in treating trabecularmeshwork and/or ocular tissue in general;

U.S. Pat. No. 6,423,682, issued Jul. 23, 2002 and U.S. Pat. No.6,485,920, issued Nov. 26, 2002, the entire contents of both of whichare incorporated herein by reference, disclose the compositions of novelhuman growth factor antagonist proteins and active variants thereof,isolated polynucleotides encoding such polypeptides, includingrecombinant DNA molecules, cloned genes or degenerate variants thereof,especially naturally occurring variants such as allelic variants,antisense polynucleotide molecules, and antibodies that specificallyrecognize one or more epitopes present on such polypeptides, as well ashybridomas producing such antibodies function of mitochondria and toxicsubstances synthesized as a metabolic byproduct within mitochondria ofcells. It is proposed that such compositions with known effects onmitochondrial stability might be effective in treating trabecularmeshwork. An antagonistic drug to neutralize the toxic byproduct or astabilizing drug to effect mitochondrial stability is believed able torestore the mitochondria function and subsequently mitigate thedysfunction of the trabecular meshwork;

U.S. Pat. No. 6,379,882, issued Apr. 30, 2002, the entire contents ofwhich are incorporated herein by reference, discloses a method forreducing cellular damage related to myocardial infarction, glaucoma oranother neurodegenerative disease by administering to a subject, atherapeutically effective amount of a test compound as determined by therelative efficacy of the test compound in reducing cell death due to theischemic condition in an in vitro assay of growth factor oroxygen/glucose and growth factor-deprived retinal ganglion cells. In thepresent invention, the in vitro cell death of growth factor oroxygen/glucose and growth factor-deprived retinal ganglion cellsgenerally occurs by an apoptotic or necrotic mechanism, wherein the testcompound comprises a calcium channel blocker, an N-methyl-D-aspartate,and a bis-benzimidazole;

U.S. Pat. No. 6,489,305, issued Dec. 3, 2002, the entire contents ofwhich are incorporated herein by reference, discloses a method forinhibiting proliferation of ocular fibroblasts or for amelioratingglaucoma surgery failure in a mammal, the method comprisingadministering to an eye of the mammal during or after glaucoma surgery ap21 cyclin dependent kinase inhibitor, wherein the cyclin dependentkinase inhibitor is administered as a polypeptide or as a nucleotidesequence that encodes the cyclin dependent kinase inhibitor administeredin an adenoviral viral vector or administered on a sponge depot;

U.S. Pat. No. 6,455,283, issued Sep. 24, 2002, the entire contents ofwhich are incorporated herein by reference, discloses a method ofvascular endothelial growth factor-E (VEGF-E). VEGF-E is a novelpolypeptide related to vascular endothelial growth factor (VEGF) andbone morphogenetic protein 1. VEGF-E has homology to VEGF includingconservation of the amino acids required for activity of VEGF. VEGF-Ecan be useful in wound repair, as well as in the generation andregeneration of tissue. It is proposed that such VEGF, VEGF-E and theirrespective antagonists with known effects on tissue regeneration oranti-regeneration might be effective in treating trabecular meshwork orocular tissue in general;

U.S. Pat. No. 6,476,211, issued Nov. 5, 2002, the entire contents ofwhich are incorporated herein by reference, discloses human CD39-likeprotein polynucleotides isolated from cDNA libraries of human fetalliver-spleen and macrophage as well as polypeptides encoded by thesepolynucleotides and mutants or variants thereof. CD39 (cluster ofdifferentiation 39) is a cell-surface molecule recognized by a “cluster”of monoclonal antibodies that can be used to identify the lineage orstage of differentiation of lymphocytes and thus to distinguish oneclass of lymphocytes from another. It is proposed that such CD39polynucleotides with known effects on antibody specifics might beeffective in treating trabecular meshwork or ocular tissue in general;

U.S. Pat. No. 5,780,052, issued Jul. 14, 1998, the entire contents ofwhich are incorporated herein by reference, discloses a method ofsalvaging a target cell from cell death, comprising contacting a targetcell having a disrupted cell membrane with a specific affinityreagent-liposome conjugate in an amount effective and for a timesufficient to allow the conjugate to prevent cell death due to membranedisruption. The patent discloses methods of delivering a selected agentinto a damaged target cell for diagnosis and therapy, wherein theconjugate comprises a biological agent selected from the groupconsisting of fibroblastic growth factor-β, angiogenic factors, highenergy substrates for the myocardium, antioxidants, cytokines andcontrast agents, which might be effective in treating trabecularmeshwork or ocular tissue in general;

U.S. Pat. No. 6,475,724, issued Nov. 5, 2002, the entire contents ofwhich are incorporated herein by reference, discloses a method oftreating glaucoma which comprises administering to a glaucomatouspatient an effective amount of an agent that inhibits the synthesis if aTIGR (trabecular meshwork inducible glucocorticoid response) protein orgene, which might be effective in treating trabecular meshwork or oculartissue in general;

U.S. Pat. No. 6,475,784, issued Nov. 5, 2002, the entire contents ofwhich are incorporated herein by reference, discloses a method forpolypeptides having anti-angiogenic activity and nucleic acids thatencode these polypeptides. The anti-angiogenic polypeptides include atleast kringles 1-3 of plasminogen. The patent '784 also provides methodsof using the polypeptides and nucleic acids for inhibiting angiogenesisand other conditions characterized by undesirable endothelial cellproliferation. Angiostatin, which is an angiogenesis inhibitor, is anaturally occurring internal cleavage product of plasminogen, whereinhuman plasminogen has five characteristic protein domains called“kringle structures.” It is proposed that such angiostatin with knowneffects on inhibiting angiogenesis might be effective in treatingtrabecular meshwork and/or ocular tissue in general;

U.S. Pat. No. 6,436,703, issued Aug. 20, 2002, the entire contents ofwhich are incorporated herein by reference, discloses a method andcompositions comprising novel isolated polypeptides, novel isolatedpolynucleotides encoding such polypeptides, including recombinant DNAmolecules, cloned genes or degenerate variants thereof, especiallynaturally occurring variants such as allelic variants, antisensepolynucleotide molecules, and antibodies that specifically recognize oneor more epitopes present on such polypeptides, as well as hybridomasproducing such antibodies. The compositions in '703 additionally includevectors, including expression vectors, containing the polynucleotides ofthe invention, cells genetically engineered to contain suchpolynucleotides and cells genetically engineered to express suchpolynucleotides, any of which might be effective in treating trabecularmeshwork and/or ocular tissue in general;

U.S. Pat. No. 6,451,764, issued Sep. 17, 2002, the entire contents ofwhich are incorporated herein by reference, discloses a method oftreating vascular tissue and promoting angiogenesis in a mammalcomprising administering to the mammal an effective amount of thecomposition comprising VRP (vascular endothelial growth factor-relatedprotein). The disclosure '764 further provides a method for treatingtrauma affecting the vascular endothelium comprising administering to amammal suffering from the trauma an effective amount of the compositioncontaining the VRP, or a method for treating a dysfunctional statecharacterized by lack of activation or lack of inhibition of a receptorfor VRP in a mammal. It is proposed that such angiogenesis promoter andits antagonists with known effects on promoting or inhibitingangiogenesis might be effective in treating trabecular meshwork and/orocular tissue in general; and

U.S. Pat. No. 5,986,168, issued Nov. 16, 1999, the entire contents ofwhich are incorporated herein by reference, discloses a prosthesisartificially made in vitro and comprising a time dependent immobilizedand insoluble bioabsorbable substance shaped into a prosthetic shape forimplantation into a mammal, and having physical means for immobilizingand insolubilizing of the bioabsorbable substance for a predeterminedperiod of time after implantation, wherein the prosthesis may comprisefibroblast growth factors, which fibroblast growth factors or theirantagonists might be effective in treating trabecular meshwork and/orocular tissue in general.

Scar-Retarding (Antifibrotic) Substances and Background

It was reported that Monoclonal antibodies are a promising modality forprevention of scarring after trabeculectomy, according to a currentresearch (OCULAR SURGERY NEWS Sep. 19, 2002 entitled TGF-beta may helpprevent postop scarring). Several studies are investigating theinteraction between growth factors and their role in the induction ofpostoperative scarring of the filtering bleb. Wimmer and colleagues notein the September issue of Der Ophthalmologe that among the growthfactors being studied in several trials, TGF-beta 2 plays a keyregulatory function. Its concentration in the aqueous humor of patientswith primary open-angle glaucoma is significantly elevated, and both invivo and in vitro studies have shown the growth factor to demonstrate“promising inhibition of scarring after subconjunctival application.” Inaddition, current research indicates the growth factor is a safe andwell-tolerated approach to managing postop scarring. It is one aspect ofthe present invention to provide a growth factor (TGF-beta 2 and thelike) to trabecular meshwork at an effective amount to mitigate,eliminate, or retard scar formation at or around the trabecularmeshwork. It is a further aspect of the present invention to provide amethod of direct delivery of at least one growth factor (TGF-beta,including TGF-beta 2, analog, derivatives and the like) to trabecularmeshwork at an effective amount to mitigate, eliminate, or retard scarformation at or around the trabecular meshwork to ocular tissue throughan ocularly inserted apparatus or an implant, including a “fistula.” Inone aspect, the bioactive agent of the invention comprises a scarretarding substance.

U.S. Pat. No. 5,324,508, issued Jun. 28, 1994, the entire contents ofwhich are incorporated herein by reference, discloses a macrophagemonokine product having a molecular weight of no more than about 10,000Dalton, wherein the macrophage monokine appears to be generallyeffective in inhibiting scar tissue. It is one object of the presentinvention to incorporate the macrophage monokine product onto atrabecular stent for scar management.

Prof. Peng Khaw (of the Institute of Ophthalmology and Moorfields EyeHospital) discloses that injecting a neutralizing antibody to theprotein transforming growth factor beta₂ (TGF-b₂) after glaucoma surgeryreduced the scarring that is the primary cause for poor postoperativeIOP control in a pilot clinical study conducted at Moorfields EyeHospital and the Western Eye Hospital. Scarring after surgery is themain cause of treatment failures, but the attempt to diminish scarringwith anti-cancer drugs can lead to its own set of problems.

Anti-cancer drugs used with glaucoma surgery, which to date haveincluded 5-fluorouracil (5FU) and mitomycin-C, can lead to the creationof acellular, thin, cystic drainage blebs that may leak, resulting inhypotony and potentially blinding infections. Anti-cancer drugs work bykilling cells, so they have a lot of potential side effects. Therefore,they are not the ideal treatment, particularly if you want to optimizethe pressure lowering in every patient having surgery.

Scarring processes are a big problem in the eye and surroundingstructures. Scarring plays a part in either the primary disease ortreatment failure of most blinding conditions in the world today. Anexception to this repair response is found in the fetal stage, whenscarring is minimal. Instead, regeneration primarily occurs. This isassociated with low levels of TGF-b in the womb.

It is therefore one aspect of the present invention to provide a methodof maintaining a fistula in trabecular meshwork with a scar-retardingsubstance for re-establishing physiologic outflow in the eye. In oneembodiment, the fistula is biodegradable.

U.S. Pat. No. 5,922,369, entire contents of which are incorporatedherein by reference, discloses a method of treating eye conditions withhuman leukocyte elastase (HLE) inhibitory agents. More specifically, itis one object of the present invention to provide a method of reducingtissue or corneal scarring comprising delivery of human leukocyteelastase inhibitory agents an effective amount for scar reducing of afree or polymer-bound HLE inhibitory agent to ocular tissue through anocularly inserted apparatus or an implant, including a fistula.

FIG. 65 shows one embodiment for a fistula without a lumen fortransporting aqueous. The fistula may be made of a soft flexiblematerial with special surface characteristics to facilitate aqueoustransporting along its surface. The material may be selected from agroup consisting of silicone, polyurethane, acrylics, and the like. Thespecial surface characteristics for facilitating aqueous transportationmay include hydrophilicity, hydrophobicity, surface charge, heparinizedsurface, surface pH, and drug-coated surface. The surfacecharacteristics may also include mechanical or physical properties suchas surface elasticity, surface configuration, shape memory and the like.FIG. 65 shows a fistula 466 comprising a proximal terminal means 467sized and shaped to be received within the anterior chamber 20 and adistal terminal means 468 sized and shaped to be received withinSchlemm's canal 22. A majority of the surface 469 with specialcharacteristics contacts the trabecular meshwork 21 where thefacilitated aqueous transportation takes places. The cross-sectionalconfiguration may be any shape, including circular, oval, star, random,and arbitrary or the like.

Some aspects of the invention provides a trabecular bypass stent that isimplantable within an eye, the device comprising: an inlet sectionhaving an inlet end exposed to an anterior chamber; an outlet sectionhaving an outlet end exposed to Schlemm's canal, wherein the device isconfigured to permit fluid entering the inlet end and then exiting theoutlet end; and at least one bioactive agent is loaded onto the stent,wherein the bioactive agent is selected from a group consisting ofTGF-beta, a gene, a growth factor, a scar-retarding (or scar-mitigating,scar-limiting, scar-inhibiting) substance. In one aspect of theinvention, the therapy combines at least one bioactive agent loaded ontoa trabecular bypass stent and a topically administered IOP-lowering eyedrop medicine selected from a group consisting (1) Miotics (e.g.,pilocarpine, carbachol, and acetylcholinesterase inhibitors), (2)Sympathomimetics (e.g., epinephrine and dipivalylepinephxine), (3)Beta-blockers (e.g., betaxolol, levobunolol and timolol), (4) Carbonicanhydrase inhibitors (e.g., acetazolamide, methazolamide andethoxzolamide), and (5) Prostaglandins (e.g., metabolite derivatives ofarachidonic acid).

Although preferred embodiments of the invention have been described indetail, including devices loaded with TGF-beta and/or bioactive agents,certain variations and modifications will be apparent to those skilledin the art, including embodiments that do not provide all of thefeatures and benefits described herein. Accordingly, the scope of thepresent invention is not to be limited by the illustrations or theforegoing descriptions thereof, but rather solely by reference to theappended claims and their equivalents.

What is claimed is:
 1. A method of treating an ocular disorder,comprising: introducing an implant into an anterior chamber of an eye;implanting the implant into eye tissue adjacent the anterior chambersuch that a proximal end of the implant resides in the anterior chamberfollowing implantation; eluting a therapeutic agent from the implantinto the eye; and controlling release of the therapeutic agent from theimplant.